Novel physiologically active substances

ABSTRACT

The present invention relates to a compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     (wherein, R 3 , R 6 , R 7  and R 21  are the same as or different from one another and each represents a hydroxyl group etc.), a pharmacologically acceptable salt thereof or a hydrate of them. The compound (I) of the present invention suppresses angiogenesis, in particular, suppresses VEGF production in a hypoxic condition and is useful as a therapeutic agent for treating solid cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 37 C.F.R. §1.53(b) continuation of U.S.patent application Ser. No. 11/473,201 filed Jun. 23, 2006, which is acontinuation of Ser. No. 10/515,647 filed Jul. 20, 2005, each of whichclaim priority on Japanese Patent Application No. 2002-155853, filed May29, 2002, Japanese Patent Application No. 2002-223355 filed on Jul. 31,2002, and Japanese Patent Application No. 2003-63176 filed on Mar. 10,2003, the entire contents of which are hereby incorporated by referenceand for which priority is claimed under 35 U.S.C. § 120.

TECHNICAL FIELD

The present invention relates to a 12-membered ring macrolide compounduseful as a medicament, preparation thereof and use thereof.

BACKGROUND OF THE INVENTION

Compounds having cytotoxicity have been used as antitumor agents, andmany screenings have been carried out using cytotoxicity as an index. Asa result, most of pre-existing antitumor agents give affection to cancercells and simultaneously to normal tissues in which a proliferation ofcell is active, for example, to bone marrow, intestine epithelium andthe like. Thus, the improvement of QOL of patients has not beensufficiently accomplished yet.

Further, although it can be expected that treatments by the antitumoragents are rather effective for leukemia, it cannot be always said thatthey are effective for solid cancer. Therefore strong demands have beenmade to provide antitumor agents that are effective for solid cancer andare highly safe.

Screenings for fermentation products of microorganism have been carriedout using the cytotoxicity in vitro as an index, expecting that theymight also be used as antitumor agents. Many compounds havingcytotoxicity have been found, however, most of them show cytotoxicactivities only in vitro, and few compounds of them show antitumoractivities in vivo, and very few compounds exhibit effectiveness forsolid cancer.

DISCLOSURE OF THE INVENTION

It is the object of the present invention to find out compounds whichshow antitumor activity not only in vitro but also in vivo and haveantitumor activities for solid cancer from fermentation products ofmicroorganism or derivatives thereof.

It is considered that tumorgenesis of a normal cell is caused bymutation of a gene in the cell occurs and an abnormal gene is expressed.Accordingly, the present inventors have made intensive investigationsbased on the inference that the growth of a tumor cell can be suppressedby changing the gene expression of the tumor cell, namely, the growth ofthe tumor cell can be controlled by changing the gene expression ofoncogene or tumor suppressor gene, or by changing the gene expressioninvolved in cell cycle. The present inventors have considered that acompound changing of the gene expression, in particular, a compoundsuppressing VEGF (vascular endothelial growth factor) production at ahypoxic condition could suppress angiogenesis by a tumor and has anantitumor activities for solid cancer. Then, they carried out screeningfor fermentation products of microorganism and derivatives thereof usingthe VEGF production by U251 cell under hypoxic stimulation as an index.As the results, the inventors have found out novel physiologicallyactive compounds, 12-membered ring macrolide compounds, named 11107 andanalogues thereof which suppress the VEGF production at a hypoxiccondition in vitro, and further suppress the growth of solid tumor cellsin vivo.

The present inventors have further found that 11107D among the 11107analogues is stable even in an aqueous solution, and that compoundsobtained by chemical modifications of 11107D (hereinafter, these arereferred to as 11107D derivatives) inherit the property of stability inan aqueous solution from 11107D and inhibit the growth of solid tumorcells in vivo experiments in much more degree. The present invention hasbeen accomplished based on these findings.

As a related art of a 12-membered ring macrolide compound which is moststructurally similar to the compounds of the present invention, a12-membered ring macrolide compound FD-895 (JP-A 4-352783) representedby the formula (XIV):

is mentioned. The publication discloses that FD-895 has in vitro cellgrowth inhibitory activities against P388 mouse leukemia cell, L-1210mouse leukemia cell and HL-60 human leukemia cell in RPM-1640 medium(column 6, Table 2). However, it has been reported that FD-895 did notshow antitumor activities in an in vivo experiment using P388 mouseleukemia cell (Seki-Asano M. et al, J. Antibiotics, 47, 1395-1401,1994).

In addition, FD-895 is unstable in an aqueous solution as describedlater and is expected to be inappropriate to mix with an infusionsolution upon administration. Thus, it cannot be said that FD-895 hassufficient qualities as an antitumor agent.

That is, the present invention relates to:

(1) a compound represented by the formula (I):

(in the formula, R³, R⁶, R⁷ and R²¹ are the same as or different fromone another and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R³, R⁶, R⁷ and R²¹ is bound, provided that R⁶ islimited to a hydroxyl group,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,

4) an optionally substituted C₇₋₂₂ aralkyloxy group,

5) an optionally substituted 5 to 14-membered heteroaralkyloxy group,

6) RCO—O— (wherein R represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted 5 to 14-membered heteroaryl group,    -   f) an optionally substituted C₇₋₂₂ aralkyl group,    -   g) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   h) an optionally substituted C₁₋₂₂ alkoxy group,    -   i) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   j) an optionally substituted C₆₋₁₄ aryloxy group or    -   k) an optionally substituted 5 to 14-membered heteroaryloxy        group),

7) R^(S1)R^(S2)R^(S3)SiO— (wherein R^(S1), R^(S2) and R^(S3) are thesame as or different from one another and each represents

-   -   a) a C₁₋₆ alkyl group or    -   b) a C₆₋₁₄ aryl group),

8) a halogen atom,

9) R^(N1)R^(N2)N—R^(M)— (wherein R^(M) represents

-   -   a) a single bond,    -   b) —CO—O—,    -   c)—SO₂—O—,    -   d) —CS—O— or    -   e) —CO—NR^(N3)— (wherein R^(N3) represents a hydrogen atom or an        optionally substituted C₁₋₆ alkyl group), provided that each of        the leftmost bond in b) to e) is bound to the nitrogen atom; and        R^(N1) and R^(N2) are the same as or different from each other        and each represents    -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted aliphatic C₂₋₂₂ acyl group,    -   e) an optionally substituted aromatic C₇₋₁₅ acyl group,    -   f) an optionally substituted C₆₋₁₄ aryl group,    -   g) an optionally substituted 5 to 14-membered heteroaryl group,    -   h) an optionally substituted C₇₋₂₂ aralkyl group,    -   i) an optionally substituted C₁₋₂₂ alkylsulfonyl group,    -   j) an optionally substituted C₆₋₁₄ arylsulfonyl group,    -   k) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group formed by R^(N1) and R^(N2) together with the        nitrogen atom to which R^(N1) and R^(N2) are bound, and the        non-aromatic heterocyclic group may have substituents,    -   l) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   m) an optionally substituted C₃₋₁₄ cycloalkyl group or    -   n) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group),

10) R^(N4)SO₂—O— (wherein R^(N4) represents

-   -   a) an optionally substituted C₁₋₂₂ alkyl group,    -   b) an optionally substituted C₆₋₁₄ aryl group,    -   c) an optionally substituted C₁₋₂₂ alkoxy group,    -   d) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   e) an optionally substituted C₆₋₁₄ aryloxy group,    -   f) an optionally substituted 5 to 14-membered heteroaryloxy        group,    -   g) an optionally substituted C₇₋₂₂ aralkyloxy group or    -   h) an optionally substituted 5 to 14-membered heteroaralkyloxy        group),

11) (R^(N5))₂PO—O— (wherein R^(N5) represents

-   -   a) an optionally substituted C₁₋₂₂ alkyl group,    -   b) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   c) an optionally substituted C₆₋₁₄ aryl group,    -   d) an optionally substituted 5 to 14-membered heteroaryl group,    -   e) an optionally substituted C₇₋₂₂ aralkyl group or    -   f) an optionally substituted 5 to 14-membered heteroaralkyl        group),

12) (R^(N1)R^(N2)N)₂PO—O— (wherein R^(N1) and R^(N2) have the samemeanings as defined above) or

13) (R^(N1)R^(N2)N)(R^(N5)O)PO—O— (wherein R^(N1), R^(N2) and R^(N5)have the same meanings as defined above), provided that a compound inwhich R³, R⁶, R⁷ and R²¹ are all hydroxyl groups, and a compound inwhich R³, R⁶ and R²¹ are all hydroxyl groups and R⁷ is an acetoxy groupare excluded), a pharmacologically acceptable salt thereof or a hydrateof them;

(2) the compound described in (1) represented by the formula (I-a):

(in the formula, R^(3a), R^(6a), R^(7a) and R^(21a) are the same as ordifferent from one another and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(3a), R^(6a), R^(7a) and R^(21a) is bound, providedthat R^(6a) is limited to a hydroxyl group,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) R^(a)CO—O— (wherein R^(a) represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted 5 to 14-membered heteroaryl group,    -   f) an optionally substituted C₇₋₂₂ aralkyl group,    -   g) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   h) an optionally substituted C₁₋₂₂ alkoxy group,    -   i) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   j) an optionally substituted C₆₋₁₄ aryloxy group or    -   k) an optionally substituted 5 to 14-membered heteroaryloxy        group),

4) R_(aS1)R^(aS2)R^(aS3)SiO— (wherein R^(aS1), R^(aS2) and R^(aS3) arethe same as or different from one another and each represents

-   -   a) a C₁₋₆ alkyl group or    -   b) a C₆₋₁₄ aryl group),

5) a halogen atom or

6) R^(aN1)R^(aN2)N—R^(aM)— (wherein Ram represents

-   -   a) a single bond,    -   b) —CO—O—,    -   c) —SO₂—O—,    -   d) —CS—O— or    -   e) —CO—NR^(aN3)— (wherein R^(aN3) represents a hydrogen atom or        an optionally substituted C₁₋₆ alkyl group, provided that each        of the leftmost bond in b) to e) is bound to the nitrogen atom);        and        R^(aN1) and R^(aN2) are the same as or different from each other        and each represents    -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted aliphatic C₂₋₂₂ acyl group,    -   e) an optionally substituted aromatic C₇₋₁₅ acyl group,    -   f) an optionally substituted C₆₋₁₄ aryl group,    -   g) an optionally substituted 5 to 14-membered heteroaryl group,    -   h) an optionally substituted C₇₋₂₂ aralkyl group,    -   i) an optionally substituted C₁₋₂₂ alkylsulfonyl group,    -   j) an optionally substituted C₆₋₁₄ arylsulfonyl group,    -   k) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group formed by R^(aN1) and R^(aN2) together with        the nitrogen atom to which R^(aN1) and R^(aN2) are bound, and        the non-aromatic heterocyclic group may have substituents,    -   l) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   m) an optionally substituted C₃₋₁₄ cycloalkyl group or    -   n) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group)), a pharmacologically acceptable salt        thereof or a hydrate of them;

(3) the compound described in (1) represented by the formula (I-b):

(in the formula, R^(3b), R^(b6), R^(b7) and R^(21b) are the same as ordifferent from one another and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(3b), R^(6b), R^(7b) and R^(21b) is bound, providedthat R^(6b) is limited to a hydroxyl group,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) R^(b)CO—O— (wherein R^(b) represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted 5 to 14-membered heteroaryl group,    -   f) an optionally substituted C₇₋₂₂ aralkyl group,    -   g) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   h) an optionally substituted C₁₋₂₂ alkoxy group,    -   i) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   j) an optionally substituted C₆₋₁₄ aryloxy group or    -   k) an optionally substituted 5 to 14-membered heteroaryloxy        group),

4) R^(bS1)R^(bS2)R^(bS3)SiO— (wherein R^(bS1), R^(bS2) and R^(bS3) arethe same as or different from one another and each represents

-   -   a) a C₁₋₆ alkyl group or    -   b) a C₆₋₁₄ aryl group) or

5) R^(bN1)R^(bN2)N—R^(bM) (wherein R^(bM) represents

-   -   a) —CO—O— or    -   b) —CS—O—, provided that each of the leftmost bond in a) and b)        is bound to the nitrogen atom; and        R^(bN1) and R^(bN2) are the same as or different from each other        and each represents    -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted aliphatic C₂₋₂₂ acyl group,    -   e) an optionally substituted aromatic C₇₋₁₅ acyl group,    -   f) an optionally substituted C₆₋₁₄ aryl group,    -   g) an optionally substituted 5 to 14-membered heteroaryl group,    -   h) an optionally substituted C₇₋₂₂ aralkyl group,    -   i) an optionally substituted C₁₋₂₂ alkylsulfonyl group,    -   j) an optionally substituted C₆₋₁₄ arylsulfonyl group,    -   k) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group formed by R^(bN1) and R^(bN2) together with        the nitrogen atom to which R^(bN1) and R^(bN2) are bound, and        the non-aromatic heterocyclic group may have substituents,    -   l) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   m) an optionally substituted C₃₋₁₄ cycloalkyl group or    -   n) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group)), a pharmacologically acceptable salt        thereof or a hydrate of them;

(4) the compound described in (1) represented by the formula (I-c):

(in the formula, R^(c3), R^(c6), R^(c7) and R^(21c) are the same as ordifferent from one another and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(3c), R^(6c), R^(7c) and R^(21c) is bound, providedthat R^(6c) is limited to a hydroxyl group,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) R^(c)CO—O— (wherein R^(c) represents

-   -   a) an optionally substituted C₁₋₂₂ alkyl group,    -   b) an optionally substituted C₆₋₁₄ aryl group,    -   c) an optionally substituted C₇₋₂₂ aralkyl group or    -   d) an optionally substituted C₆₋₁₄ aryloxy group),

4) R^(cS1)R^(cS2)R^(cS3)SiO— (wherein R^(cS1), R^(cS2) and R^(cS3) arethe same as or different from one another and each represents

-   -   a) a C₁₋₆ alkyl group or    -   b) a C₆₋₁₄ aryl group) or

5) R^(cN1)R^(cN2)N—R^(cM)— (wherein R^(cM) represents

-   -   a) —CO—O— or    -   b) —CS—O—, provided that each of the leftmost bond in a) and b)        is bound to the nitrogen atom; and        R^(cN1) and R^(cN2) are the same as or different from each other        and each represents    -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group formed by R^(cN1) and R^(cN2) together with        the nitrogen atom to which R^(cN1) and R^(cN2) are bound, and        the non-aromatic heterocyclic group may have substituents,    -   d) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   e) an optionally substituted C₃₋₁₄ cycloalkyl group or    -   f) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group, and the non-aromatic heterocyclic group may        have substituents)), a pharmacologically acceptable salt thereof        or a hydrate of them;

(5) the compound described in (1) represented by the formula (I-d):

(in the formula, R^(3d) represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which R^(3d) is bound,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,

4) an optionally substituted C₇₋₂₂ aralkyloxy group,

5) R^(d)CO—O— (wherein R^(d) represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted 5 to 14-membered heteroaryl group,    -   f) an optionally substituted C₇₋₂₂ aralkyl group,    -   g) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   h) an optionally substituted C₁₋₂₂ alkoxy group,    -   i) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   j) an optionally substituted C₆₋₁₄ aryloxy group or    -   k) an optionally substituted 5 to 14-membered heteroaryloxy        group) or

6) R^(dN1)R^(dN2)N—CO—O— (wherein R^(dN1) and R^(dN2) are the same as ordifferent from each other and each represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₂₂ alkyl group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted 5 to 14-membered heteroaryl group,    -   f) an optionally substituted C₇₋₂₂ aralkyl group,    -   g) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   h) an optionally substituted C₃₋₁₄ cycloalkyl group,    -   i) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group or    -   j) an optionally substituted 3 to 14-membered non-aromatic        heterocyclic group formed by R^(dN1) and R^(dN2) together with        the nitrogen atom to which R^(dN1) and R^(dN2) are bound, and        the non-aromatic heterocyclic group may have substituents); and        R^(d6), R^(d7) and R^(21d) are the same as or different from one        another and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(6d), R^(7d) and R^(21d) is bound, provided thatR^(6d) is limited to a hydroxyl group,

2) an optionally substituted C₁₋₂₂ alkoxy group,

3) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,

4) an optionally substituted C₇₋₂₂ aralkyloxy group,

5) R^(d)CO—O— (wherein R^(d) has the same meaning as defined above),

6) R^(dN1)R^(dN2)N—CO—O— (wherein R^(dN1) and R^(dN2) have the samemeanings as defined above),

7) R^(dN1)R^(dN2)N—SO₂—O— (wherein R^(dN1) and R^(dN2) have the samemeanings as defined above),

8) R^(dN1)R^(dN2)N—CS—O— (wherein R^(dN1) and R^(dN2) have the samemeanings as defined above),

9) R^(dN3)SO₂—O— (wherein R^(dN3) represents

-   -   a) an optionally substituted C₁₋₂₂ alkyl group,    -   b) an optionally substituted C₁₋₂₂ alkoxy group,    -   c) an optionally substituted unsaturated C₂₋₂₂ alkoxy group,    -   d) an optionally substituted C₆₋₁₄ aryl group,    -   e) an optionally substituted C₆₋₁₄ aryloxy group,    -   f) an optionally substituted 5 to 14-membered heteroaryloxy        group,    -   g) an optionally substituted C₇₋₂₂ aralkyloxy group or    -   h) an optionally substituted 5 to 14-membered heteroaralkyloxy        group),

10) (R^(dN5)O)₂PO— (wherein R^(dN5) represents

-   -   a) an optionally substituted C₁₋₂₂ alkyl group,    -   b) an optionally substituted unsaturated C₂₋₂₂ alkyl group,    -   c) an optionally substituted C₆₋₁₄ aryl group,    -   d) an optionally substituted 5 to 14-membered heteroaryl group,    -   e) an optionally substituted C₇₋₂₂ aralkyl group or    -   f) an optionally substituted 5 to 14-membered heteroaralkyl        group),

11) (R^(dN1)R^(dN2)N)₂PO— (wherein R^(dN1) and R^(dN2) have the samemeanings as defined above) or

12) (R^(dN1)R^(dN2)N)(R^(dN5)O)PO— (wherein R^(dN1), R^(dN2) and R^(dN5)have the same meanings as defined above), provided that a compound inwhich R^(3d), R^(6d), R^(7d) and R^(21d) are all hydroxyl groups, and acompound in which R^(3d), R^(6d) and R^(21d) are hydroxyl groups andR^(7d) is an acetoxy group are excluded), a pharmacologically acceptablesalt thereof or a hydrate of them;

(6) the compound described in (1), wherein R⁶ and/or R⁷ representsR^(N1)R^(N2)N—R^(M)— (wherein R^(M) represents

-   -   a) —CO—O— or    -   b) —CS—O—; and        R^(N1) and R^(N2) have the same meanings as defined above,        provided that each of the leftmost bond in a) and b) is bound to        the nitrogen atom), a pharmacologically acceptable salt thereof        or a hydrate of them;

(7) the compound described in (1), a pharmacologically acceptable saltthereof or a hydrate of them, wherein R²¹ is an oxo group formedtogether with the carbon atom to which R²¹ is bound;

(8) the compound described in (5) represented by the formula (I-e):

(in the formula, R^(3e) and R^(21e) are the same as or different fromeach other and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(3e) and R^(21e) is bound,

2) an optionally substituted C₁₋₆ alkoxy group,

3) an optionally substituted unsaturated C₂₋₁₀ alkoxy group,

4) an optionally substituted C₇₋₁₀ aralkyloxy group,

5) an optionally substituted aliphatic C₂₋₆ acyloxy group or

6) R^(eN1)R^(eN2)N—CO—O— (wherein R^(eN1) and R^(eN2) are the same as ordifferent from each other and each represents

-   -   A) a hydrogen atom or    -   B) an optionally substituted C₁₋₆ alkyl group); and        R^(6e) and R^(7e) are the same as or different from each other        and each represents

1) a hydroxyl group or an oxo group formed together with the carbon atomto which each of R^(6e) and R^(7e) is bound, provided that R^(6e) islimited to a hydroxyl group,

2) an optionally substituted C₁₋₆ alkoxy group,

3) an optionally substituted unsaturated C₂₋₁₀ alkoxy group,

4) an optionally substituted C₇₋₁₀ aralkyloxy group,

5) an optionally substituted aliphatic C₂₋₆ acyloxy group or

6) R^(e)C(═Y^(e))—O— (wherein Y^(e) represents an oxygen atom or asulfur atom; and R^(e) represents

-   -   a) a hydrogen atom,    -   b) an optionally substituted C₁₋₆ alkyl group,    -   c) an optionally substituted C₇₋₁₀ aralkyl group,    -   d) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   e) the formula (III):

(in the formula,

-   -   A) n represents an integer of 0 to 4;        X_(e) represents    -   i) —CHR^(eN4)—,    -   ii) —NR^(eN5)—,    -   iii) —O—,    -   iv) —S—,    -   v) —SO— or    -   vi) —SO₂—;        R^(eN1) represents    -   i) a hydrogen atom or    -   ii) a C₁₋₆ alkyl group;        R^(eN2) represents    -   i) hydrogen atom or    -   ii) a C₁₋₆ alkyl group;        R^(eN3) and R^(eN4) are the same as or different from each other        and each represents    -   i) a hydrogen atom,    -   ii) an optionally substituted C₁₋₆ alkyl group,    -   iii) an optionally substituted unsaturated C₂₋₁₀ alkyl group,    -   iv) an optionally substituted C₆₋₁₄ aryl group,    -   v) an optionally substituted 5 to 14-membered heteroaryl group,    -   vi) an optionally substituted C₇₋₁₀ aralkyl group,    -   vii) an optionally substituted C₃₋₈ cycloalkyl group,    -   viii) an optionally substituted C₄₋₉ cycloalkyl alkyl group,    -   ix) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   x) an optionally substituted 5 to 14-membered non-aromatic        heterocyclic group,    -   xi) —NR^(eN6)R^(eN7) (wherein R^(eN6) and R^(eN7) are the same        as or different from each other and each represents a hydrogen        atom or an optionally substituted C₁₋₆ alkyl group) or    -   xii) an optionally substituted 5 to 14-membered non-aromatic        heterocyclic group formed by R^(eN3) and R^(eN4) together with        the carbon atom to which R^(eN3) and R^(eN4) are bound, and the        non-aromatic heterocyclic group may have substituents; and        R^(eN5) represents    -   i) a hydrogen atom,    -   ii) an optionally substituted C₁₋₆ alkyl group,    -   iii) an optionally substituted unsaturated C₂₋₁₀ alkyl group,    -   iv) an optionally substituted C₆₋₁₄ aryl group,    -   v) an optionally substituted 5 to 14-membered heteroaryl group,    -   vi) an optionally substituted C₇₋₁₀ aralkyl group,    -   vii) an optionally substituted C₃₋₈ cycloalkyl group,    -   viii) an optionally substituted C₄₋₉ cycloalkyl alkyl group,    -   ix) an optionally substituted 5 to 14-membered heteroaralkyl        group,    -   x) an optionally substituted 5 to 14-membered non-aromatic        heterocyclic group or    -   xi) an optionally substituted 5 to 14-membered non-aromatic        heterocyclic group formed by R^(eN3) and R^(eN5) together with        the nitrogen atom to which R^(eN3) and R^(eN5) are bound, and        the non-aromatic heterocyclic group may have substituents,    -   B) X_(e), n, R^(eN3), R^(eN4) and R^(eN5) each represents the        group as defined above; and R^(eN1) and R^(eN2) together form an        optionally substituted 5 to 14-membered non-aromatic        heterocyclic group,    -   C) X_(e), n, R^(eN2), R^(eN4) and R^(eNn5) each represents the        group as defined above; and R^(eN1) and R^(eN3) together form an        optionally substituted 5 to 14-membered non-aromatic        heterocyclic group or    -   D) X_(e), n, R_(eN1), R^(eN4) and R^(eN5) each represents the        group as defined above; and R^(eN2) and R^(eN3) together form an        optionally substituted 5 to 14-membered non-aromatic        heterocyclic group) or    -   f) the formula (IV):

(in the formula, R^(eN8) and R^(eN9) are the same as or different fromeach other and each represents

-   -   i) a hydrogen atom,    -   ii) an optionally substituted C₁₋₆ alkyl group,    -   iii) an optionally substituted C₆₋₁₄ aryl group,    -   iv) an optionally substituted 5 to 14-membered heteroaryl group,    -   v) an optionally substituted C₇₋₁₀ aralkyl group or    -   vi) an optionally substituted 5 to 14-membered heteroaralkyl        group))), a pharmacologically acceptable salt thereof or a        hydrate of them;

(9) the compound described in (5), wherein R^(6d) and/or R^(7d)represents R^(d1)C(═Y^(d1))—O— (wherein Y^(d1) represents an oxygen atomor a sulfur atom; and R_(d1) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted C₇₋₁₀ aralkyl group or

4) an optionally substituted 5 to 14-membered heteroaralkyl group), apharmacologically acceptable salt thereof or a hydrate of them;

(10) the compound described in (5), wherein R^(6d) and/or R^(7d)represents R^(d2)C(═Y^(d2))—O— (wherein Y^(d2) represents an oxygen atomor a sulfur atom; and R^(d2) represents the formula (III′):

(in the formula, n represents an integer of 0 to 4; X₁ represents

1) —CHR^(dN7),

2) —NR^(dN8),

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—;

R^(dN4) and R^(dN5) are the same as or different from each other andeach represents

1) a hydrogen atom or

2) a C₁₋₆ alkyl group;

R^(dN6) and R^(dN7) are the same as or different from each other andeach represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group,

10) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup,

11)-NR^(dN9)R^(dN10) (wherein R^(dN9) and R^(dN10) are the same as ordifferent from each other and each represents a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group) or

12) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup formed together by R^(dN6) and R^(dN7), and the non-aromaticheterocyclic group may have substituents; and

R^(dN8) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group,

10) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup,

11) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup formed by R^(dN4), R^(dN5) or R^(dN6) together with the nitrogenatom to which each of R^(dN4), R^(dN5) and R^(dN6) is bound, and thenon-aromatic heterocyclic group may have substituents or

12) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup formed by two substituents selected from the group consisting ofR^(dN4), R^(dN5) and R^(dN6) together with the nitrogen atom to which itis bound, and the non-aromatic heterocyclic group may havesubstituents)), a pharmacologically acceptable salt thereof or a hydrateof them;

(11) the compound described in (10), a pharmacologically acceptable saltthereof or a hydrate of them, wherein X₁ represents —NR^(dN8)— (whereinNR^(dN8) has the same meanings as defined above);

(12) the compound described in (5) represented by the formula (I-f):

(in the formula, R^(7f) represents R^(f)C(═Y^(f))—O— (wherein Y^(f)represents an oxygen atom or a sulfur atom; and R^(f) represents theformula (V):

(wherein n represents an integer of 0 to 4;R^(fN1) represents

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group; and

R^(fN2) represents

1) a hydrogen atom,

2) a methylamino group,

3) a dimethylamino group,

4) an ethylamino group,

5) a diethylamino group,

6) an ethylmethylamino group,

7) a pyridinyl group,

8) a pyrrolidin-1-yl group,

9) a piperidin-1-yl group,

10) a morpholin-4-yl group or

11) a 4-methylpiperazin-1-yl group))), a pharmacologically acceptablesalt thereof or a hydrate of them;

(13) the compound described in (5), wherein R^(6d) and/or R^(7d)represents R^(d3)CO—O— (wherein R^(d3) represents the formula (VI):

(wherein n₁ and n₂ are the same as or different from each other and eachrepresents an integer of 0 to 4;X₂ represents

1) —CHR^(dN13)—,

2) —NR^(dN14)—,

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—;

R^(dN11) represents

1) a hydrogen atom or

2) an optionally substituted C₁₋₆ alkyl group;

R^(dN12) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted C₆₋₁₄ aryl group or

4) an optionally substituted C₇₋₁₀ aralkyl group;

R^(dN13) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group,

10) —NR^(dN15)R^(dN16) (wherein R^(dN15) and R^(dN16) are the same as ordifferent from each other and each represents a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group) or

11) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup; and R^(dN14) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group or

10) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup)), a pharmacologically acceptable salt thereof or a hydrate ofthem;

(14) the compound described in (5) represented by the formula (I-g):

(in the formula, R^(7g) represents R^(g)CO—O— (wherein R^(g) representsthe formula (VII):

(wherein n₃ represents 1 or 2;R^(dN17) represents

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group; and

R^(dN18) represents

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group))), a pharmacologically acceptable salt thereof or ahydrate of them;

(15) the compound described in (5), wherein R^(6d) and/or R^(7d)represents R^(d4)CO—O—

(wherein R^(d4) represents the formula (VIII):

(wherein n₁ and n₂ are the same as or different from each other and eachrepresents an integer of 0 to 4;X₃ represents

1) —CHR^(dN21)—,

2) —NR^(dN22),

3) —O—,

4) —S—,

5) —SO— or

6) —SO₂—;

R^(dN19) represents

1) a hydrogen atom or

2) a C₁₋₆ alkyl group;

R^(dN20) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted C₆₋₁₄ aryl group or

4) an optionally substituted C₇₋₁₀ aralkyl group;

R^(dN21) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₁₋₆ alkoxy group,

5) an optionally substituted C₆₋₁₄ aryl group,

6) an optionally substituted 5 to 14-membered heteroaryl group,

7) an optionally substituted C₇₋₁₀ aralkyl group,

8) an optionally substituted C₃₋₈ cycloalkyl group,

9) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

10) an optionally substituted 5 to 14-membered heteroaralkyl group,

11) —NR^(dN23)R^(dN24) (wherein R^(dN23) and R^(dN24) are the same as ordifferent from each other and each represents a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group) or

12) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup; and

R^(dN22) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group or

10) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup)), a pharmacologically acceptable salt thereof or a hydrate ofthem;

(16) the compound described in (5) represented by the formula (I-h):

(in the formula, R^(7h) represents R^(h)CO—O— (wherein R^(h) representsthe formula (IX):

(wherein n₄ represents an integer of 1 to 3; andR^(dN25) represents

1) an amino group,

2) a methylamino group,

3) a dimethylamino group,

4) a pyrrolidin-1-yl group,

5) a piperidin-1-yl group or

6) a morpholin-4-yl group))), a pharmacologically acceptable saltthereof or a hydrate of them;

(17) the compound described in (5) represented by the formula (I-i):

(in the formula, R^(7i) represents R^(i)CO—O— (wherein R^(i) representsthe formula (X):

(wherein n₄ represents an integer of 1 to 3;R^(dN26) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted C₆₋₁₄ aryl group or

4) an optionally substituted C₇₋₁₀ aralkyl group; and

R^(dN27) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted C₃₋₈ cycloalkyl group,

4) an optionally substituted 3 to 8-membered non-aromatic heterocyclicgroup,

5) an optionally substituted C₆₋₁₄ aryl group,

6) an optionally substituted 5 to 14-membered heteroaryl group,

7) an optionally substituted C₇₋₁₀ aralkyl group,

8) an optionally substituted 5 to 14-membered heteroaralkyl group or

9) an optionally substituted C₄₋₉ cycloalkyl alkyl group))), apharmacologically acceptable salt thereof or a hydrate of them;

(18) the compound described in (5) represented by the formula (I-j):

(in the formula, R^(7j) represents R^(j)CO—O— (wherein R^(j) representsthe formula (XI):

(wherein n₄ represents an integer of 1 to 3; andR^(dN28) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) a C₃₋₈ cycloalkyl group,

4) a C₄₋₉ cycloalkyl alkyl group,

5) a C₇₋₁₀ aralkyl group,

6) a pyridinyl group or

7) a tetrahydropyranyl group))), a pharmacologically acceptable saltthereof or a hydrate of them;

(19) the compound described in (5) represented by the formula (I-k):

(in the formula, R^(7k) represents R^(k)CO—O— (wherein R^(k) representsthe formula (XII):

(wherein m₁, m₂, m₃ and m₄ are the same as or different from one anotherand each represents 0 or 1;n₄ represents an integer of 1 to 3; andR^(dN29) represents

1) a hydrogen atom,

2) an optionally substituted C₁₋₆ alkyl group,

3) an optionally substituted unsaturated C₂₋₁₀ alkyl group,

4) an optionally substituted C₆₋₁₄ aryl group,

5) an optionally substituted 5 to 14-membered heteroaryl group,

6) an optionally substituted C₇₋₁₀ aralkyl group,

7) an optionally substituted C₃₋₈ cycloalkyl group,

8) an optionally substituted C₄₋₉ cycloalkyl alkyl group,

9) an optionally substituted 5 to 14-membered heteroaralkyl group or

10) an optionally substituted 5 to 14-membered non-aromatic heterocyclicgroup))), a pharmacologically acceptable salt thereof or a hydrate ofthem;

(20) the compound described in (5) represented by the formula (I-m):

(in the formula, R^(7m) represents R^(m)CO—O— (wherein R^(m) representsthe formula (XIII):

(wherein m₅ represents an integer of 1 to 3; and n₅ represents 2 or3))), a pharmacologically acceptable salt thereof or a hydrate of them;

(21) the compound described in (5) represented by the formula (I-n):

(in the formula, R^(7n) represents R^(n)CO—O— (wherein R^(n) is a grouprepresented by the formula (XIV):

a pharmacologically acceptable salt thereof or a hydrate of them;

(22) the compound described in (1), which is selected from:(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 6);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 9);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12);(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 16);(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 21);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 25);(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 26);(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 27);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 31);(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 36);(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 38);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44);(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 45);(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 75);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 54);(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 63);(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 64);(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85);(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 109);(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 69); and(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 131);

(23) the compound described in (1), which is selected from:(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 9);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12);(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 26);(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44);(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-olide(Compound 45); and(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 75);

(24) a medicament comprising the compound described in any one of (1) to(23), a pharmacologically acceptable salt thereof or a hydrate of themas an active ingredient;

(25) a pharmaceutical composition comprising the compound described inany one of (1) to (23), a pharmacologically acceptable salt thereof or ahydrate of them as an active ingredient;

(26) the medicament described in (24), which is an agent for preventingor treating a disease against which a regulation of gene expression isefficacious;

(27) the medicament described in (24), which is an agent for preventingor treating a diseases against which suppression of VEGF production isefficacious;

(28) the medicament described in (24), which is an agent for preventingor treating a disease against which an antiangiogenic effect isefficacious;

(29) the medicament described in (24), which is an angiogenesisinhibitor;

(30) the medicament described in (24), which is an antitumor agent;

(31) the medicament described in (24), as a therapeutic agent fortreating angioma;

(32) the medicament described in (24), which is a cancer metastasisinhibitor;

(33) the medicament described in (24), which is a therapeutic agent fortreating retinal neovascularization or diabetic retinopathy;

(34) the medicament described in (24), which is a therapeutic agent fortreating inflammatory disease;

(35) the medicament described in (24), which is a therapeutic agent fortreating inflammatory diseases consisting of deformans arthritis,rheumatoid arthritis, psoriasis and delayed hypersensitivity reaction;

(36) the medicament described in (24), which is a therapeutic agent fortreating atherosclerosis;

(37) the medicament described in (24), which is a therapeutic agent fortreating solid cancer;

(38) the medicament described in (37), wherein the solid cancer is lungcancer, brain tumor, breast cancer, prostate cancer, ovarian cancer,colon cancer or melanoma;

(39) the medicament described in (24), which is a therapeutic agent fortreating leukemia;

(40) the medicament described in (24), which is an antitumor agent basedon a regulation of gene expression;

(41) the medicament described in (24), which is an antitumor agent basedon suppression of VEGF production;

(42) the medicament described in (24), which is an antitumor agent basedon an effect of angiogenesis inhibition;

(43) a method for preventing or treating a disease against which aregulation of gene expression is efficacious, which comprisesadministering a pharmacologically effective dose of the medicamentdescribed in (24) to a patient;

(44) a method for preventing or treating a disease against whichsuppression of VEGF production is efficacious, which comprisesadministering a pharmacologically effective dose of the medicamentdescribed in (24) to a patient;

(45) a method for preventing or treating a disease against which anangiogenesis inhibition is efficacious, which comprises administering apharmacologically effective dose of the medicament described in (24) toa patient;

(46) use of the compound described in any one of (1) to (23), apharmacologically acceptable salt thereof or a hydrate of them, formanufacturing an agent for preventing or treating a disease againstwhich a regulation of gene expression is efficacious;

(47) use of the compound described in any one of (1) to (23), apharmacologically acceptable salt thereof or a hydrate of them, formanufacturing an agent for preventing or treating a disease againstwhich suppression of VEGF production is efficacious;

(48) use of the compound described in any one of (1) to (23), apharmacologically acceptable salt thereof or a hydrate of them, formanufacturing an agent for preventing or treating a disease againstwhich an angiogenesis inhibition is efficacious; and

(49) use of the compound described in any one of (1) to (23), apharmacologically acceptable salt thereof or a hydrate of them, forproducing an agent for preventing or treating solid cancers.

The terms, symbols and the like used in the present specification willbe illustrated below.

In the present specification, the chemical formula of the compoundaccording to the present invention is illustrated as a planimetricchemical formula for convenience but the compound can include certainisomers drawn from the chemical formula. The present invention caninclude all isomers and mixtures of the isomers such as a geometricisomer which is generated from the configuration of the compound, anoptical isomer based on an asymmetric carbon, a rotamer, a stereoisomerand a tautomer. The present invention is not limited to the expedientialdescription of the chemical formula, and can include either of isomersor a mixture thereof. Accordingly, when the compound of the presentinvention has an asymmetric carbon in the molecule, and its opticallyactive substance and racemate exist, any one is included. Further, whenpolymorphic crystals exist, the crystal form of the present invention isnot specifically limited to one form, and any one of the crystal formsmay be single or a mixture of the crystal forms. The compoundrepresented by the formula (I) according to the present invention or asalt thereof may be an anhydrate or a hydrate, and both are included inthe present invention. The metabolite which is generated in vivo bydecomposition of the compound of the formula (I) according to thepresent invention and the prodrug of the compound of the formula (I)according to the present invention or a salt thereof are also includedin the present invention.

The “halogen atom” used in the specification of the present applicationmeans a fluorine atom, a chlorine atom, a bromine atom and an iodineatom. Among them, for example, a fluorine atom, a chlorine atom or abromine atom is preferred, of which a fluorine atom or a chlorine atomis typically preferred.

The “C₁₋₂₂ alkyl group” used in the specification of the presentapplication indicates a linear or branched alkyl group having 1 to 22carbon atoms, such as methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropylgroup, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group, 3-methylpentyl group, n-heptyl group,n-octyl group, n-nonyl group or n-decyl group; preferably a linear orbranched alkyl group having 1 to 6 carbon atoms, such as methyl group,ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butylgroup, sec-butyl group, tert-butyl group or n-pentyl group; and morepreferably, for example, methyl group, ethyl group, propyl group,iso-propyl group, n-butyl group, iso-butyl group or tert-butyl group.

The “unsaturated C₂₋₂₂ alkyl group” used in the specification of thepresent application indicates a linear or branched alkenyl group having2 to 22 carbon atoms or a linear or branched alkynyl group having 2 to22 carbon atoms, such as vinyl group, allyl group, 1-propenyl group,isopropenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group,1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group,1-hexenyl group, 1,3-hexadienyl group, 1,5-hexadienyl group, ethynylgroup, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup, 3-butynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-butynylgroup, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group or1,5-hexanediynyl group. It preferably indicates a linear or branchedalkenyl group having 2 to 10 carbon atoms or a linear or branchedalkynyl group having 2 to 10 carbon atoms, such as vinyl group, allylgroup, 1-propenyl group, 2-propenyl group, isopropenyl group,3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, ethynylgroup, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup, 3-butynyl group or 3-methyl-1-propynyl group.

The “C₆₋₁₄ aryl group” used in the specification of the presentapplication means an aromatic cyclic hydrocarbon group having 6 to 14carbon atoms, and a monocyclic group and condensed rings such as abicyclic group and a tricyclic group are included. Examples thereof arephenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group,azulenyl group, heptalenyl group, indacenyl group, acenaphthyl group,fluorenyl group, phenalenyl group, phenanthrenyl group and anthracenylgroup; of which a preferred example is phenyl group, 1-naphthyl group or2-naphthyl group.

The “5 to 14-membered heteroaryl group” used in the specification of thepresent application means a monocyclic, bicyclic or tricyclic 5 to14-membered aromatic heterocyclic group which contains one or more ofhetero atoms selected from the group consisting of nitrogen atom, sulfuratom and oxygen atom. Preferred examples thereof are anitrogen-containing aromatic heterocyclic group such as pyrrolyl group,pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group,triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolylgroup, imidazolyl group, benzimidazolyl group, indolyl group, isoindolylgroup, indolizinyl group, purinyl group, indazolyl group, quinolinylgroup, isoquinolinyl group, quinolizinyl group, phthalazinyl group,naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinylgroup, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinylgroup, acridinyl group, phenanthridinyl group, carbazolyl group,carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenazinylgroup, imidazopyridinyl group, imidazopyrimidinyl group,pyrazolopyridinyl group or pyrazolopyridinyl group; a sulfur-containingaromatic heterocyclic group such as thienyl group or benzothienyl group;and an oxygen-containing aromatic heterocyclic group such as furylgroup, pyranyl group, cyclopentapyranyl group, benzofuryl group orisobenzofuryl group; an aromatic heterocyclic group containing two ormore different hetero atoms, such as thiazolyl group, isothiazolylgroup, benzothiazolyl group, benzthiadiazolyl group, phenothiazinylgroup, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolylgroup, isoxazoyl group, benzoxazolyl group, oxadiazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group,furopyrrolyl group or pyridoxazinyl group, of which a preferred exampleis thienyl group, furyl group, pyridinyl group, pyridazinyl group,pyrimidinyl group or pyrazinyl group.

The “3 to 14-membered non-aromatic heterocyclic group” used in thespecification of the present application indicates a monocyclic,bicyclic or tricyclic 3 to 14-membered non-aromatic heterocyclic groupwhich may contain one or more hetero atoms selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom. Preferredexamples thereof are aziridinyl group, azetidinyl group, pyrrolidinylgroup, pyrrolyl group, piperidinyl group, piperazinyl group,homopiperidinyl group, homopiperazinyl group, imidazolyl group,pyrazolidinyl group, imidazolidinyl group, morpholinyl group,thiomorpholinyl group, imidazolinyl group, oxazolinyl group,2,5-diazabicyclo[2.2.1]heptyl group, 2,5-diazabicyclo[2.2.2]octyl group,3,8-diazabicyclo[3.2.1]octyl group, 1,4-diazabicyclo[4.3.0]nonyl group,quinuclidinyl group, tetrahydrofuranyl group and tetrahydrothiophenylgroup. The non-aromatic heterocyclic group also includes a group derivedfrom a pyridone ring, and a non-aromatic fused ring (e.g., a groupderived from, for example, phthalimide ring or succinimide ring).

The “C₇₋₂₂ aralkyl group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₁₋₂₂alkyl group” of which substitutable moiety is replaced by theabove-defined “C₆₋₁₄ aryl group”. Specific examples thereof are benzylgroup, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group,1-naphthylmethyl group and 2-naphthylmethyl group, of which an aralkylgroup having 7 to 10 carbon atoms such as benzyl group or phenethylgroup is preferred.

The “5 to 14-membered heteroaralkyl group” used in the specification ofthe present application means a group corresponding to the above-defined“C₁₋₂₂ alkyl group” of which substitutable moiety is replaced by theabove-defined “5 to 14-membered heteroaryl group”. Specific examplesthereof are thienylmethyl group, furylmethyl group, pyridinylmethylgroup, pyridazinylmethyl group, pyrimidinylmethyl group andpyrazinylmethyl group, of which a preferred example is thienylmethylgroup, furylmethyl group or pyridinylmethyl group.

The “C₃₋₁₄ cycloalkyl group” used in the specification of the presentapplication indicates a cycloalkyl group having 3 to 14 carbon atoms,and suitable examples thereof are cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctylgroup, of which a preferred example is cyclopentyl group, cyclohexylgroup, cycloheptyl group or cyclooctyl group.

The “C₄₋₉ cycloalkyl alkyl group” used in the specification of thepresent application means a group corresponding to the above-defined“C₁₋₂₂ alkyl group” of which substitutable moiety is replaced by theabove-defined “C₃₋₁₄ cycloalkyl group”. Specific examples thereof arecyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethylgroup, cyclohexylmethyl group, cycloheptylmethyl group andcyclooctylmethyl group, of which a preferred example iscyclopropylmethyl group, cyclobutylmethyl group or cyclopentylmethylgroup.

The “C₁₋₂₂ alkoxy group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₁₋₂₂alkyl group” to which end an oxygen atom is bonded. Suitable examplesthereof are methoxy group, ethoxy group, n-propoxy group, iso-propoxygroup, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxygroup, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group,n-hexyloxy group, iso-hexyloxy group, 1,1-dimethylpropoxy group,1,2-dimethylpropoxy group, 2,2-dimethylpropoxy group,1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group,1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxygroup, 2,3-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2-ethylbutoxygroup, 2-methylpentyloxy group, 3-methylpentyloxy group and hexyloxygroup, of which a preferred example is methoxy group, ethoxy group,n-propoxy group, iso-propoxy group, iso-butoxy group or2,2-dimethylpropoxy group.

The “unsaturated C₂₋₂₂ alkoxy group” used in the specification of thepresent application means a group corresponding to the above-defined“unsaturated C₂₋₂₂ alkyl group” to which end an oxygen atom is bonded.Suitable examples thereof are vinyloxy group, allyloxy group,1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group,2-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 1-butenyloxygroup, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group,1-hexenyloxy group, 1,3-hexadienyloxy group, 1,5-hexadienyloxy group,propargyloxy group and 2-butynyloxy group, of which a preferred exampleis allyloxy group, propargyloxy group or 2-butynyloxy group.

The “C₆₋₁₄ aryloxy group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₆₋₁₄ arylgroup” to which end an oxygen atom is bonded. Specific examples thereofare phenyloxy group, indenyloxy group, 1-naphthyloxy group,2-naphthyloxy group, azulenyloxy group, heptalenyloxy group,indacenyloxy group, acenaphthyloxy group, fluorenyloxy group,phenalenyloxy group, phenanthrenyloxy group and anthracenyloxy group, ofwhich a preferred example is phenyloxy group, 1-naphthyloxy group or2-naphthyloxy group.

The “C₇₋₂₂ aralkyloxy group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₇₋₂₂aralkyl group” to which end an oxygen atom is bonded. Specific examplesthereof are benzyloxy group, phenethyloxy group, 3-phenylpropyloxygroup, 4-phenylbutyloxy group, 1-naphthylmethyloxy group and2-naphthylmethyloxy group, of which a preferred example is benzyloxygroup.

The “5 to 14-membered heteroaralkyloxy group” used in the specificationof the present application means a group corresponding to theabove-defined “5 to 14-membered heteroaralkyl group” to which end anoxygen atom is bonded. Specific examples thereof are thienylmethyloxygroup, furylmethyloxy group, pyridinylmethyloxy group,pyridazinylmethyloxy group, pyrimidinylmethyloxy group andpyrazinylmethyloxy group, of which a preferred example isthienylmethyloxy group, furylmethyloxy group or pyridinylmethyloxygroup.

The “5 to 14-membered heteroaryloxy group” used in the specification ofthe present application means a group corresponding to the above-defined“5 to 14-membered heteroaryl group” to which end an oxygen atom isbonded. Specific examples thereof are pyrrolyloxy group, pyridinyloxygroup, pyridazinyloxy group, pyrimidinyloxy group, pyrazinyloxy group,triazolyloxy group, tetrazolyloxy group, benzotriazolyloxy group,pyrazolyloxy group, imidazolyloxy group, benzimidazolyloxy group,indolyloxy group, isoindolyloxy group, indolizinyloxy group, purinyloxygroup, indazolyloxy group, quinolinyloxy group, isoquinolinyloxy group,quinolizinyloxy group, phthalazinyloxy group, naphthyridinyloxy group,quinoxalinyloxy group, quinazolinyloxy group, cinnolinyloxy group,pteridinyloxy group, imidazotriazinyloxy group, pyrazinopyridazinyloxygroup, acridinyloxy group, phenanthridinyloxy group, carbazolyloxygroup, carbazolinyloxy group, perimidinyloxy group, phenanthrolinyloxygroup, phenazinyloxy group, imidazopyridinyloxy group,imidazopyrimidinyloxy group, pyrazolopyridinyloxy group,pyrazolopyridinyloxy group, thienyloxy group, benzothienyloxy group,furyloxy group, pyranyloxy group, cyclopentapyranyloxy group,benzofuryloxy group, isobenzofuryloxy group, thiazolyloxy group,isothiazolyloxy group, benzothiazolyloxy group, benzothiadiazolyloxygroup, phenothiazinyloxy group, isoxazolyloxy group, furazanyloxy group,phenoxazinyloxy group, oxazolyloxy group, isoxazolyloxy group,benzoxazolyloxy group, oxadiazolyloxy group, pyrazolooxazolyloxy group,imidazothiazolyloxy group, thienofuranyloxy group, furopyrrolyloxy groupand pyridoxazinyloxy group, of which a preferred example is thienyloxygroup, pyridinyloxy group, pyrimidinyloxy group or pyrazinyloxy group.

The “aliphatic C₂₋₂₂ acyl group” used in the specification of thepresent application means a group corresponding to the above-defined“C₁₋₂₂ alkyl group” or “unsaturated C₂₋₂₂ alkyl group” to which end acarbonyl group is bonded. Examples thereof are acetyl group, propionylgroup, butyryl group, iso-butyryl group, valeryl group, iso-valerylgroup, pivaloyl group, caproyl group, decanoyl group, lauroyl group,myristoyl group, palmitoyl group, stearoyl group, arachidoyl group,acryloyl group, propioloyl group, crotonoyl group, iso-crotonoyl group,oleoyl group and linolenoyl group, of which a preferred example is anacyl group having 2 to 6 carbon atoms, such as acetyl group, propionylgroup, butyryl group, iso-butyryl group or acryloyl group.

The “aromatic C₇₋₁₅ acyl group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₆₋₁₄ arylgroup” or “5 to 14-membered heteroaryl group” to which end a carbonylgroup is bonded. Examples thereof are benzoyl group, 1-naphthoyl group,2-naphthoyl group, picolinoyl group, nicotinoyl group, isonicotinoylgroup, furoyl group and thiophenecarbonyl group, of which a preferredexample is benzoyl group, picolinoyl group, nicotinoyl group orisonicotinoyl group.

The “C₁₋₂₂ alkylsulfonyl group” used in the specification of the presentapplication means a sulfonyl group to which the above-defined “C₁₋₂₂alkyl group” is bound. Specific examples thereof are methanesulfonylgroup, ethanesulfonyl group, n-propanesulfonyl group andiso-propanesulfonyl group, of which a preferred example ismethanesulfonyl group.

The “C₆₋₁₄ arylsulfonyl group” used in the specification of the presentapplication means a sulfonyl group to which the above-defined “C₆₋₁₄aryl group” is bound. Specific examples thereof are benzenesulfonylgroup, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group, ofwhich a preferred example is benzenesulfonyl group.

The “aliphatic C₂₋₂₂ acyloxy group” used in the specification of thepresent application means a group corresponding to the above-defined“aliphatic C₂₋₂₂ acyl group” to which end an oxygen atom is bonded.Specific examples thereof are acetoxy group, propionyloxy group andacryloxy group, of which a preferred example is acetoxy group orpropionyloxy group.

The “C₂₋₂₂ alkoxycarbonyl group” used in the specification of thepresent application means a group corresponding to the above-defined“C₁₋₂₂ alkoxy group” to which end a carbonyl group is bonded. Examplesthereof are methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonylgroup, iso-butoxycarbonyl group, sec-butoxycarbonyl group andtert-butoxycarbonyl group, of which a preferred example isethoxycarbonyl group, iso-propoxycarbonyl group or tert-butoxycarbonylgroup.

The “unsaturated C₃₋₂₂ alkoxycarbonyl group” used in the specificationof the present application means a group corresponding to theabove-defined “unsaturated C₂₋₂₂ alkoxy group” to which end a carbonylgroup is bonded. Examples thereof are vinyloxycarbonyl group,allyloxycarbonyl group, 1-propenyloxycarbonyl group,isopropenyloxycarbonyl group, propargyloxycarbonyl group and2-butynyloxycarbonyl group, of which a preferred example isallyloxycarbonyl group.

The “C₁₋₂₂ alkylthio group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₁₋₂₂alkyl group” to which end a sulfur atom is bonded. Examples thereof aremethylthio group, ethylthio group, n-propylthio group and iso-propylthiogroup, of which a preferred example is methylthio group or ethylthiogroup.

The “C₁₋₂₂ alkylsulfinyl group” used in the specification of the presentapplication means a group corresponding to the above-defined “C₁₋₂₂alkyl group” to which end a sulfinyl group is bonded. Examples thereofare methanesulfinyl group, ethanesulfinyl group, n-propanesulfinyl groupand iso-propanesulfinyl group, of which a preferred example ismethanesulfinyl group or ethanesulfinyl group.

The “C₁₋₂₂ alkylsulfonyloxy group” used in the specification of thepresent application means a group corresponding to the above-defined“C₁₋₂₂ alkylsulfonyl group” to which end an oxygen atom is bonded.Examples thereof are methanesulfonyloxy group, ethanesulfonyloxy group,n-propanesulfonyloxy group and iso-propanesulfonyloxy group, of which apreferred example is methanesulfonyloxy group.

The substituent of the phrase “an optionally substituted” used in thespecification of the present application may be one or more groupsselected from:

(1) a halogen atom,(2) a hydroxyl group,(3) a thiol group,(4) a nitro group,(5) a nitroso group,(6) a cyano group,(7) a carboxyl group,(8) a hydroxysulfonyl group,(9) a amino group,(10) a C₁₋₂₂ alkyl group (for example, methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,sec-butyl group and tert-butyl group),(11) an unsaturated C₂₋₂₂ alkyl group (for example, vinyl group, allylgroup, 1-propenyl group, 2-propenyl group, isopropenyl group, ethynylgroup, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynylgroup and 3-butynyl group),(12) a C₆₋₁₄ aryl group (for example, phenyl group, 1-naphthyl group and2-naphthyl group),(13) a 5 to 14-membered heteroaryl group (for example, thienyl group,furyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group andpyrazinyl group),(14) a 3 to 14-membered non-aromatic heterocyclic group (for example,aziridinyl group, azetidyl group, pyrrolidinyl group, pyrrolyl group,piperidinyl group, piperazinyl group, homopiperidinyl group,homopiperazinyl group, imidazolyl group, pyrazolidinyl group,imidazolidinyl group, morpholinyl group, thiomorpholinyl group,imidazolinyl group, oxazolinyl group and quinuclidinyl group),(15) a C₃₋₁₄ cycloalkyl group (for example, cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl groupand cyclooctyl group),(16) a C₁₋₂₂ alkoxy group (for example, methoxy group, ethoxy group,n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group,iso-butoxy group and tert-butoxy group),(17) an unsaturated C₂₋₂₂ alkoxy group (for example, vinyloxy group,allyloxy group, 1-propenyloxy group, 2-propenyloxy group, isopropenyloxygroup, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group,1-butynyloxy group and 2-butynyloxy group),(18) a C₆₋₁₄ aryloxy group (for example, phenyloxy group, 1-naphthyloxygroup and 2-naphthyloxy group),(19) a C₇₋₂₂ aralkyloxy group (for example, benzyloxy group,phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group,1-naphthylmethyloxy group and 2-naphthylmethyloxy group),(20) a 5 to 14-membered heteroaralkyloxy group (for example,thienylmethyloxy group, furylmethyloxy group, pyridinylmethyloxy group,pyridazinylmethyloxy group, pyrimidinylmethyloxy group andpyrazinylmethyloxy group),(21) a 5 to 14-membered heteroaryloxy group (for example, thienyloxygroup, furyloxy group, pyridinyloxy group, pyridazinyloxy group,pyrimidinyloxy group and pyrazinyloxy group),(22) an aliphatic C₂₋₂₂ acyl group (for example, acetyl group, propionylgroup, butyryl group, iso-butyryl group, valeryl group, iso-valerylgroup, pivaloyl group, caproyl group, decanoyl group, lauroyl group,myristoyl group, palmitoyl group, stearoyl group, arachidoyl group,acryloyl group, propioloyl group, crotonoyl group, iso-crotonoyl group,oleoyl group and linolenoyl group),(23) an aromatic C₇₋₁₅ acyl group (for example, benzoyl group,1-naphthoyl group and 2-naphthoyl group),(24) an aliphatic C₂₋₂₂ acyloxy group (for example, acetoxy group,propionyloxy group and acryloxy group),(25) a C₂₋₂₂ alkoxycarbonyl group (for example, methoxycarbonyl group,ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonylgroup, n-butoxycarbonyl group, iso-butoxycarbonyl group,sec-butoxycarbonyl group and tert-butoxycarbonyl group),(26) an unsaturated C₃₋₂₂ alkoxycarbonyl group (for example,vinyloxycarbonyl group, allyloxycarbonyl group, 1-propenyloxycarbonylgroup, 2-propenyloxycarbonyl group, isopropenyloxycarbonyl group,propargyloxycarbonyl group and 2-butynyloxycarbonyl group),(27) a C₁₋₂₂ alkylthio group (for example, methylthio group, ethylthiogroup, n-propylthio group and iso-propylthio group),(28) a C₁₋₂₂ alkylsulfinyl group (for example, methanesulfinyl group,ethanesulfinyl group, n-propanesulfinyl group and iso-propanesulfinylgroup),(29) a C₁₋₂₂ alkylsulfonyl group (for example, methanesulfonyl group,ethanesulfonyl group, n-propanesulfonyl group and iso-propanesulfonylgroup),(30) a C₆₋₁₄ arylsulfonyl group (for example, benzenesulfonyl group,1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group),(31) a C₁₋₂₂ alkylsulfonyloxy group (for example, methanesulfonyloxygroup, ethanesulfonyloxy group, n-propanesulfonyloxy group andiso-propanesulfonyloxy group),(32) carbamoyl group, and(33) formyl group.

Among them, a preferred example is an amino group, a C₁₋₂₂ alkyl group,an unsaturated C₂₋₂₂ alkyl group, a C₆₋₁₄ aryl group, a 5 to 14-memberedheteroaryl group, a 3 to 14-membered non-aromatic heterocyclic group anda C₃₋₁₄ cycloalkyl group, and a more preferred example is an aminogroup, a C₁₋₂₂ alkyl group, a 3 to 14-membered non-aromatic heterocyclicgroup and a C₃₋₁₄ cycloalkyl group. The above-mentioned (9) an aminogroup and (31) a carbamoyl group as the substituent in “an optionallysubstituted” may each be further substituted with one or two of a C₁₋₂₂alkyl group, an unsaturated C₂₋₂₂ alkyl group or a C₆₋₁₄ aryl group.

The compounds of the formula (I) according to the present invention willbe elucidated below.

The compounds of the formula (I) suppress VEGF production under ahypoxic condition and possess a growth inhibitory activities to solidtumor cells in in vivo. Among them, the compounds of the formula (I-a)are preferred, of which the compounds of the formula (I-b) are morepreferred and the compounds of the formula (I-c) are typicallyadvantageous.

The compounds of the formula (I) are structurally characterized by the6-position side chain and/or 7-position side chain, and the group ofmore preferred compounds can be defined as the compounds of the formula(I-d). In addition to the compounds of the formula (I-d), the compoundsof the formula (I), in which R²¹ forms an oxo group together with thecarbon atom to which R²¹ is bound, belong to the group of compoundshaving good activities. As detailed embodiments of more preferredcompounds among the compounds of the formula (I-d), the compounds of theabove-mentioned “5.” to “19.” of the present invention may beexemplified.

Preferred examples of the compounds of the formula (I) will beillustrated below. The group of the preferred compounds inclusive ofcompounds described later in Examples include, for example, Compound 6,Compound 9, Compound 12, Compound 15, Compound 16, Compound 20, Compound21, Compound 22, Compound 25, Compound 26, Compound 27, Compound 31,Compound 34, Compound 36, Compound 38, Compound 39, Compound 40,Compound 41, Compound 43, Compound 44, Compound 45, Compound 48,Compound 51, Compound 53, Compound 54, Compound 55, Compound 57,Compound 58, Compound 62, Compound 63, Compound 64, Compound 65,Compound 69, Compound 70, Compound 72, Compound 74, Compound 75,Compound 77, Compound 79, Compound 85, Compound 88, Compound 105,Compound 106, Compound 108, Compound 109 and Compound 131. Among them,examples of more preferred compounds are Compound 6, Compound 9,Compound 12, Compound 16, Compound 21, Compound 25, Compound 26,Compound 27, Compound 31, Compound 36, Compound 38, Compound 44,Compound 45, Compound 54, Compound 63, Compound 64, Compound 69,Compound 75, Compound 85, Compound 109 and Compound 131, of which, forexample, Compound 9, Compound 12, Compound 26, Compound 44, Compound 45and Compound 75 are typically preferred.

Next, the preparation of the compound of the formula (I) according tothe present invention will be illustrated.

The compound of the formula (I) can be prepared by culturing a strainbelonging to the genus Streptomyces which has an ability of producingthe bioactive substance 11107D [the compound of the formula (I), inwhich R³, R⁶ and R²¹ are hydroxyl groups, and R⁷ is an acetoxy group]under aerobic conditions, collecting the compound from the microorganismcell and culture, and chemically modifying the obtained compound as akey compound according to a conventional procedure.

Initially, the process for preparation of 11107D will be elucidatedbelow.

The following deposit microorganism strain can be used for themicroorganism for producing 11107D. The strain was internationallydeposited to International Patent Organism Depositary (IPOD) NationalInstitute of Advanced Industrial Science and Technology (Tsukuba Central6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan).Specifically, Streptomyces sp. Mer-11107 was deposited as FERM P-18144at the National Institute of Bioscience and Human-Technology Agency ofIndustrial Science and Technology (1-3, Higashi 1-chome Tsukuba-shi,Ibaraki-ken 305-8566 Japan). Further, this was transferred toInternational Deposit FERM BP-7812 at International Patent OrganismDepositary (IPOD) National Institute of Advanced Industrial Science andTechnology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi,Ibaraki-ken 305-8566 Japan).

The strain for producing 11107D is not specifically limited and alsoincludes variants of such strains, as long as the strain is belonging tothe genus Streptomyces and has an ability of producing 11107D. Examplesof the strain are Streptomyces sp. A-1532, Streptomyces sp. A-1533 andStreptomyces sp. A-1534, in addition to the above-mentioned strain.These strains were also internationally deposited to InternationalPatent Organism Depositary (IPOD) National Institute of AdvancedIndustrial Science and Technology (Tsukuba Central 6, 1-1, Higashi1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan) as FERM BP-7849, FERMBP-7850 and FERM BP-7851, respectively.

Detailed description of 1. the property of separated microorganism, 2.the fermentation method of the microorganism and 3. the purificationmethod of an active substance in the preparation of 11107D will be madebelow.

1. The Property of Separated Microorganism

As the strain for use in the present invention, it is expected that anyone of strains belonging to the genus Streptomyces and having an abilityof producing 11107D can be used. However, as a typical strain used inthe present invention, a strain which was named as “Mer-11107 strain” bythe inventors is exemplified. The taxonomical properties of this strainare as follows.

(1) Morphological Characteristics

Aerial hyphae that bore spirales is extended from vegetative hypha inthis strain. Spore chain consisting of about 10 to 20 of columnar sporesare formed at the edge of the ripened aerial hyphae. The size of thespores is about 0.7×1.0 μm, the surface of the spores is smooth, andspecific organs such as sporangium, sclerotium and flagellum are notobserved.

(2) Cultural Characteristics on Various Media

Cultural characteristics of the strain after incubation at 28° C. fortwo weeks on various media are shown below. The color tone is describedby the color name and codes which are shown in the parenthesis of theColor Harmony Manual (Container Corporation of America).

1) Yeast Extract-Malt Extract Agar Medium

The strain grew well, the aerial hyphae grew up on the surface, andlight gray spores (Light gray; d) were observed. The reverse side ofcolony was Light melon yellow (3ea). Soluble pigment was not produced.

2) Oatmeal Agar Medium

The strain grew in the middle level, the aerial hyphae grew slightly onthe surface, and gray spores (Gray; g) were observed. The reverse sideof colony was Nude tan (4gc) or Putty (1½ ec). Soluble pigment was notproduced.

3) Inorganic Salt-Starch Agar Medium

The strain grew well, the aerial hyphae grew up on the surface, and grayspores (Gray; e) were observed. The reverse side of colony was Fawn(4ig) or Gray (g). Soluble pigment was not produced.

4) Glycerol-Asparagine Agar Medium

The strain grew well, the aerial hyphae grew up on the surface, andwhite spores (White; a) were observed. The reverse side of colony wasPearl pink (3ca). Soluble pigment was not produced.

5) Peptone-Yeast Extract-Iron Agar Medium

The strain growth was bad, and the aerial hyphae did not grow on thesurface. The reverse side of colony was Light melon yellow (3ea).Soluble pigment was not produced.

6) Tyrosine Agar Medium

The strain grew well, the aerial hyphae grew up on the surface, andwhite spores (White; a) were observed. The reverse side of colony wasPearl pink (3ca). Soluble pigment was not produced.

(3) Utilization of Various Carbon Sources

Various carbon sources are added in Pridham-Gottlieb agar medium, growthof the strain after incubation at 28° C. for two weeks are shown below.

1) L-arabinose ± 2) D-xylose ± 3) D-glucose + 4) D-fructose + 5)sucrose + 6) inositol + 7) L-rhamnose − 8) D-mannitol + 9) D-raffinose +(+: positive, ±: slightly positive, −: negative)

(4) Physiological Properties

The physiological properties of the strain are as shown below.

(a) Range of growth temperature (yeast extract-malt extract agar medium,incubation for 2 weeks) 12° C. to 37° C.(b) Range of optimum temperature (yeast extract-malt extract agarmedium, incubation for 2 weeks) 21° C. to 33° C.(c) Liquefaction of gelatin (glucose-peptone-gelatin agar medium)negative(d) Coagulation of milk (skim milk agar medium) negative(e) Peptonization of milk (skim milk agar medium) negative(f) Hydrolysis of starch (inorganic salt-starch agar medium) positive(g) Formation of melanoid pigment (peptone-yeast extract-iron agarmedium) negative (tyrosine medium) negative(h) Production of hydrogen sulfide (peptone-yeast extract-iron agarmedium) negative(i) Reduction of nitrate (broth containing 0.1% potassium nitrate)negative(j) Sodium chloride tolerance (yeast extract-malt extract agar medium,incubation for 2 weeks) grown at a salt content of 4% or less

(5) Chemotaxonomy

LL-diaminopimelic acid and glycine were detected from the cell wall ofthe present strain.

It is considered that the present strain is a strain of the genusStreptomyces from the above-mentioned microbial characteristics.Accordingly, the present inventors have named the present microbialstrain as Streptomyces sp. Mer-11107 and have deposited the strain asFERM P-18144 at the National Institute of Bioscience andHuman-Technology Agency of Industrial Science and Technology.

2. Fermentation Method of Producing Microorganism

The physiologically active substance 11107D according to the presentinvention can be produced by inoculating the strain on a nutritionsource medium and carrying out aerobic fermentation. The strain forproducing the physiologically active substance 11107D is not limited tothe above-mentioned strain, and any strain belonging to the genusStreptomyces and having an ability of producing 11107D can be used inthe present invention.

The fermentation method of the above-mentioned microorganism isaccording to the general fermentation method of microorganism, but it ispreferably carried out under aerobic conditions such as shaking cultureor aeration-agitation fermentation using liquid medium. The medium usedfor culture may be a medium containing a nutrition source which can beutilized by microorganism belonging the genus Streptomyces, thereforeall of various synthetic, a semi-synthetic medium, an organic medium andthe like can be utilized. As the carbon source in the mediumcomposition, there can be used a single or a combination of glucose,sucrose, fructose, glycerin, dextrin, starch, molasses, soybean oil andthe like. As the nitrogen source, there can be used a single or acombination of organic nitrogen sources such as pharma media, peptone,meat extract, soybean powder, casein, amino acid, yeast extract andurea, and inorganic nitrogen sources such as sodium nitrate and ammoniumsulfate. Additionally, for example, there can be added and used saltssuch as sodium chloride, potassium chloride, calcium carbonate,magnesium sulfate, sodium phosphate, potassium phosphate and cobaltchloride; heavy metal salts, vitamins such as vitamin B or biotin, ifnecessary. Further, when foaming is remarkable during culture, variousdefoaming agents can be appropriately added in the medium as necessary.When the defoaming agent is added, it is required to set at aconcentration for not adversely affecting the production of an objectivesubstance, and for example, the use concentration is desirably 0.05% orless.

The culture condition can be appropriately selected within the range atwhich the microbial strain grows well and can produce theabove-mentioned substance. For example, the pH of a medium is about 5 to9, and preferably nearby neutral in general. The temperature offermentation is usually kept at 20° C. to 40° C. and preferably 28° C.to 35° C. The fermentation period is about 2 to 8 days, and usuallyabout 3 to 5 days. The above-mentioned fermentation conditions can besuitably changed in accordance with the kind and property ofmicroorganism used, external conditions and the like, and it is needlessto say that an optimum condition can be selected. The physiologicallyactive substance 11107D of the present invention which was accumulatedin the cultured broth can be collected by usual separation proceduresutilizing its property such as a solvent extraction method and anabsorbing resin method.

The physiologically active substance 11107D can also be prepared, forexample, by using a microorganism belonging to the genus Streptomyces(for example, Streptomyces sp. AB-1704 strain (FERM P-18999)) and using11107B substance (the compound described in Example A4 of WO 02/060890,as shown in Referential Examples 6 to 10.

3. Purification Method for the Bioactive Substance

General methods for separation and purification which are used forisolation of microbial metabolites from the cultured broth can beemployed in order to collect 11107D from the cultured medium after thefermentation. For example, there can be corresponded all methods such asextraction by an organic solvent typically using methanol, ethanol,butanol, ethyl acetate or chloroform; various kinds of ion-exchangechromatography; gel filtration chromatography using Sephadex LH-20; thetreatment of adsorption and desorption by absorption chromatographytypically using active carbon or silica gel or by thin layerchromatography; or high performance liquid chromatography typicallyusing a reverse phase column, to this. Further, the purification methodsfor 11107D are not specifically limited to the methods shown here.

The compound 11107D can be isolated and purified by using these methodsalone or in combination or repeatedly using them.

Next, the preparation for the compounds of the formula (I) other than11107D will be elucidated.

The compounds of the formula (I) can be synthesized from 11107D isolatedand purified as a starting compound by converting the hydroxyl groupand/or acetoxy group of the compound according to general organicsynthetic procedures. Typical examples of the synthesis methods are A. apreparation for an urethane derivative, B. a preparation for athiourethane derivative, C. a preparation for an ether derivative, D. apreparation for an ester derivative, E. a preparation for a phosphoricester or amidophosphoric ester derivative, F. a preparation for asulfuric ester or amidosulfuric ester derivative, G. a preparation for ahalogen derivative, H. a preparation for a sulfonic ester derivative, I.a preparation for an amine derivative, and J. a preparation for anoxo-derivative by oxidation of a hydroxyl group. The introduction andremoval of a protecting group for a hydroxyl group can be carried outaccording to need by the method described in document (Protective Groupsin Organic Synthesis, T. W. Greene, John Wiley & Sons, Inc. 3rd Edition)or a method analogous thereto, while depending on the type of theprotecting group and the stability of the compound relating to thepreparation. The compounds of the formula (I) can be prepared by usingthe introduction and removal reactions for the hydroxyl-protecting groupand the preparation described above in a suitable combination. Morespecifically, the compounds of the formula (I) in which R³, R⁶, R⁷ andR²¹ are the substituents listed in above-mentioned 9) can be prepared byusing the preparation for a urethane derivative, a thiourethanederivative, an amidosulfuric ester or an amine derivative; those inwhich R³, R⁶, R⁷ and R²¹ are the substituents listed in above-mentioned2) to 5) can be prepared by using the preparation for an etherderivative; those in which R³, R⁶, R⁷ and R²¹ are the substituentslisted in above-mentioned 6) can be prepared by using the preparationfor an ester derivative; those in which R³, R⁶, R⁷ and R²¹ are thesubstituents listed in above-mentioned 11) to 13) can be prepared byusing the preparation for a phosphoric ester or amidophosphoric esterderivative; those in which R³, R⁶, R⁷ and R²¹ are the substituentslisted in above-mentioned 10) can be prepared by using the preparationfor a sulfuric ester or sulfonic ester derivative; those in which R³,R⁶, R⁷ and R²¹ are the substituents listed in above-mentioned 8) can beprepared by using the preparation for a halogen derivative; those inwhich R³, R⁶, R⁷ and R²¹ are the substituents listed in above-mentioned7) can be prepared by using the introduction and removal reactions of ahydroxyl-protecting group; and the oxo-derivative in which R³, R⁶, R⁷and R²¹ are the substituents listed in above-mentioned 1) can beprepared by using the preparation for an oxo-derivative by oxidation ofa hydroxyl group.

Next, synthetic methods for preparing the compounds of the formula (I)will be elucidated.

A. A Preparation for a Urethane Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents ahydrogen atom or a protecting group, provided that R^(3A), R^(6A),R^(16A) and R^(21A) do not concurrently represent hydrogen atoms;R^(3B), R^(6B), R^(16B) and R^(21B) each represents a hydrogen atom, aprotecting group or a group represented by the formula

R^(F)O—CO— (wherein RF represents an optionally substituted C₆₋₁₄ arylgroup), provided that R^(3B), R^(6B), R^(16B) and R^(21B) do notconcurrently represent hydrogen atoms; R^(3C), R^(6C), R^(16C) andR^(21C) each represents a hydrogen atom, a protecting group or a grouprepresented by the formula R^(N1)R^(N2)N—CO— (wherein R^(N1) and R^(N2)each represents the group as defined above); and R^(3D), R^(6D), R^(16D)and R^(21D) each represents a hydrogen atom or a group represented bythe formula R^(N1)R^(N2)N—CO— (wherein R^(N1) and R^(N2) each representsthe group as defined above).

The step A1 is a step for preparing the compound of the formula (IA).This step is carried out by protecting the hydroxyl group(s) of 11107D.

The reaction for protecting the hydroxyl group(s) is carried outaccording to a procedure well known in organic synthetic chemistry,while being selected depending on the type of the protecting group.

Examples of the protecting group are 1-ethoxyethyl, tetrahydropyranyl,1-methyl-1-methoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,4-methoxytetrahydrothiopyranyl S,S-dioxide, methoxymethyl,methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl,trimethylsilylethyl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl,trimethylsilyl, triisopropylsilyl, methyl-di-tert-butylsilyl,diphenylmethylsilyl, benzyl, p-methoxybenzyl, p-methylbenzyl,p-nitrobenzyl, p-chlorobenzyl and triphenylmethyl. All or part of thehydroxyl groups can be appropriately protected by these protectinggroups.

For example, hydroxyl-protected derivatives protected by 1-ethoxyethyl,tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl or4-methoxytetrahydrothiopyranyl-S,S-dioxide can be synthesized bytreating 11107D with a corresponding vinyl ether such as ethylvinylether or dihydropyran in the presence of an acid. Examples of the acidare general acids including organic acids such as pyridiniump-toluenesulfonate (PPTS), p-toluenesulfonic acid, camphorsulfonic acid,acetic acid, trifluoroacetic acid or methanesulfonic acid; and inorganicacids such as hydrogen chloride, nitric acid, hydrochloric acid orsulfuric acid. Among them, a preferred example is pyridiniump-toluenesulfonate (PPTS), p-toluenesulfonic acid or camphorsulfonicacid. The solvent used in the reaction is not specifically limited, butan inert solvent which cannot easily react with a starting material isdesirable. Examples of such solvents are ethers such as tetrahydrofuran,diethyl ether, diisopropyl ether, dioxane and dimethoxyethane;halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride and 1,2-dichloroethane; hydrocarbons such as hexane,benzene and toluene; ketones such as acetone and methyl ethyl ketone;nitriles such as acetonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyridone and hexamethylphosphoramide;and sulfoxides such as dimethyl sulfoxide, of which a preferred exampleis dichloromethane, chloroform or tetrahydrofuran. The reaction time is10 minutes to 5 days and is preferably 1 day to 2 days. The reactiontemperature is a temperature of −78° C. to heating under reflux and ispreferably room temperature. The amounts of the vinyl ether and acidused in the reaction are 1 to 200 equivalents and 0.05 to 2 equivalents,and preferably 30 to 50 equivalents and 0.1 to 0.3 equivalent,respectively, to 11107D.

Examples of other protecting groups are methoxymethyl, methylthiomethyl,methoxyethoxymethyl, trichloroethoxymethyl, trimethylsilylethyl,trimethylsilylethoxymethyl, tert-butyldimethylsilyl, triethylsilyl,trimethylsilyl, diethylisopropylsilyl, triisopropylsilyl,di-tert-butylmethylsilyl, diphenylmethylsilyl, benzyl, p-methoxybenzyl,p-methylbenzyl, p-nitrobenzyl, p-chlorobenzyl and triphenylmethyl. Suchhydroxyl-protected derivatives can be synthesized by reacting a startingmaterial with a chloride, bromide or trifluoromethanesulfonate of therespective protecting groups in the presence of a base. The base is ageneral organic base or inorganic base. Examples of the organic base arean aromatic base such as imidazole, 4-(N,N-dimethylamino)pyridine (the4-dimethylaminopyridine, N,N-dimethylaminopyridine anddimethylaminopyridine used in the present specification have the samemeaning), pyridine, 2,6-lutidine or collidine; a tertiary amine such asN-methylpiperidine, N-methylpyrrolidine, triethylamine, trimethylamine,di-iso-propylethylamine, cyclohexyldimethylamine, N-methylmorpholine or1,8-bis(dimethylamino)naphthalene; a secondary amine such asdi-iso-butylamine or dicyclohexylamine; an alkyllithium such asmethyllithium or butyllithium; a metal alkoxide such as sodium methoxideor sodium ethoxide. Examples of the inorganic base are an alkali metalhydride such as sodium hydride or potassium hydride; an alkaline earthmetal hydride such as calcium hydride; an alkali metal hydroxide such assodium hydroxide or potassium hydroxide; an alkali metal carbonate suchas sodium carbonate, potassium carbonate or cesium carbonate; and analkali metal hydrogen carbonate such as sodium bicarbonate. Preferredexamples of the base for the protection of the hydroxyl group by a silylprotecting group are an aromatic base such as imidazole or4-dimethylaminopyridine; and a tertiary amine such as triethylamine. Thesolvent used in the reaction is not specifically limited, but one whichdoes not easily react with a starting material is desirable. Examples ofsuch solvents are the above-mentioned inert solvents, of which apreferred example is tetrahydrofuran, dichloromethane orN,N-dimethylformamide. The reaction time is 10 minutes to 3 days and ispreferably 1 day to 2 days. The reaction temperature is a temperature of−78° C. to heating under reflux and is preferably −10° C. to 50° C. Theamounts of the chloride, bromide or trifluoromethanesulfate and the baseused in the reaction are 1 to 20 equivalents and 0.5 to 30 equivalents,preferably 1 to 15 equivalents and 0.5 to 20 equivalents, respectively,to 11107D.

The hydroxyl groups of 11107D can be selectively protected by selectingthe reagent and equivalence thereof for use in the protection of thehydroxyl groups. For example, a compound in which the hydroxyl groups atthe 3-position and 21-position are selectively protected can be obtainedby carrying out the reaction at room temperature usingchlorotriethylsilane, triethylamine and 4-dimethylaminopyridine indichloromethane or using tert-butylchlorodimethylsilane and imidazole inN,N-dimethylformamide. In this procedure, for example, the hydroxylgroup at the 3-position can be selectively protected by controlling theequivalence of chlorotriethylsilane or tert-butylchlorodimethylsilane.Further, it is possible that two or three of the four hydroxyl groupsare protected by a silyl group, and then the other two or one hydroxylgroup is protected by the above-mentioned ethoxyethyl or the like.

The step A2 is a step for preparing the compound of the formula (IIA).This step is carried out by converting the acetoxy group of the compoundof the formula (IA) into the hydroxyl group by the treatment of a basein an inert solvent.

Examples of the base used herein are inorganic bases including an alkalimetal hydride such as sodium hydride or potassium hydride; an alkalineearth metal hydride such as calcium hydride; an alkali metal hydroxidesuch as lithium hydroxide, sodium hydroxide or potassium hydroxide; analkali metal carbonate such as lithium carbonate, sodium carbonate orpotassium carbonate; an alkali metal hydrogen carbonate such as sodiumbicarbonate; and a metal alkoxide such as lithium methoxide, sodiummethoxide, sodium ethoxide or potassium tert-butoxide, as well as basessuch as guanidine or ammonia. Preferred examples of the base arepotassium carbonate and guanidine.

Examples of the inert solvent used herein include, in addition to theabove-mentioned inert solvents, an alcohol solvent such as methanol,ethanol, isopropanol or tert-butanol, and water. These solvents can beused in combination as a mixture. A preferred solvent is an alcoholsolvent or a mixture of an alcohol and a halogen solvent. The reactiontime is 10 minutes to 5 days and is preferably 30 minutes to 1 day. Thereaction temperature is a temperature of −78° C. to heating under refluxand is preferably room temperature. The amount of the base used in thereaction is 1 to 10 equivalents and preferably 2 to 5 equivalents to thecompound of the formula (IA).

The step A3 is a step for preparing the compound of the formula (IIIA).This step is carried out by treating the hydroxyl group of the compoundof the formula (IIA) with a chloroformate derivative orcarbonyldiimidazole in the presence of a base. Examples of thechloroformate derivative are 4-nitrophenyl chloroformate, phenylchloroformate, 4-chlorophenyl chloroformate, 4-bromophenyl chloroformateand 2,4-dinitrophenyl chloroformate. Examples of the base are theabove-mentioned organic bases and inorganic bases, of which, forexample, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine or sodium hydride is preferably used. The solventused in the reaction is not specifically limited, but a solvent thatdoes not easily react with a starting material is desirable. Examples ofsuch solvents are the above-mentioned inert solvents, of which, forexample, tetrahydrofuran, dichloromethane or N,N-dimethylformamide ispreferably used. The amounts of the chloroformate derivative and basefor use in the reaction are 1 to 10 equivalents and 1 to 20 equivalents,and preferably 1 to 5 equivalents and 1 to 10 equivalents, respectively,to the compound of the formula (IIA). The reaction time is 10 minutes to30 hours and is preferably 1 to 4 hours. The reaction temperature is atemperature of −78° C. to heating under reflux and is preferably −10° C.to 50° C.

For the hydroxyl compound (1A) in which one to three of OR^(3A),OR^(6A), OR^(16A) and OR^(21A) have not been protected in the step A1,the hydroxyl groups can be converted into carbonic ester groups by thestep A3. More specifically, the hydroxyl groups of the compound (IA)other than the hydroxyl group at the 7-position can be converted intocarbonic ester groups by the same way as the hydroxyl group at the7-position by treatment with a base and a chloroformate derivative inequivalents corresponding to the number of hydroxyl groups to beconverted into carbonic ester groups.

The step A4 is a step for preparing the compound of the formula (IVA).This step is carried out by treating the carbonic ester of the formula(IIIA) with an amine (R^(N1)R^(N2)H) that can form a desired compound ofthe formula (I) in an inert solvent in the presence of a base or withthe amine alone.

Examples of the amine used herein are methylamine, ethylamine,propylamine, butylamine, octylamine, decylamine, cyclopropylamine,cyclopentylamine, cyclohexylamine, dimethylamine, diethylamine,ethylmethylamine, ethylenediamine, 1,3-propanediamine,1,4-butanediamine, N,N-dimethylethylenediamine,N,N-dimethyl-1,3-propanediamine, N,N-dimethyl-1,4-butanediamine,N,N-diethylethylenediamine, N,N-diethyl-1,3-propanediamine,N,N-diethyl-1,4-butanediamine, N,N,N′-trimethylethylenediamine,N,N,N′-trimethyl-1,3-propanediamine, N,N,N′-trimethyl-1,4-butanediamine,N-ethyl-N′,N′-dimethylethylenediamine,N-ethyl-N′,N′-dimethyl-1,3-propanediamine,N-ethyl-N′,N′-dimethyl-1,4-butanediamine,N,N,N′-triethylethylenediamine, N,N,N′-triethyl-1,3-propanediamine,N,N,N′-triethyl-1,4-butanediamine, N,N-diethyl-N′-methylethylenediamine,N,N-diethyl-N′-methyl-1,3-propanediamine,N,N-diethyl-N′-methyl-1,4-butanediamine,N,N′-dimethyl-N-phenylethylenediamine,N,N′-dimethyl-N-phenyl-1,3-propanediamine,N-benzyl-N,N′-dimethylethylenediamine,N-benzyl-N,N′-dimethyl-1,3-propanediamine, morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, pyrrolidine,piperidine, piperazine, homopiperazine, 4-hydroxypiperidine,4-methoxypiperidine, 1-methylpiperazine, 1-ethylpiperazine,1-propylpiperazine, 1-butylpiperazine, 1-isopropylpiperazine,1-cyclobutylpiperazine, 1-cyclopentylpiperazine, 1-cyclohexylpiperazine,1-cycloheptylpiperazine, 1-cyclooctylpiperazine,1-(cyclopropylmethyl)piperazine, 1-benzylpiperazine,1-methylhomopiperazine, 1-ethylhomopiperazine,1-(2-aminoethyl)pyrrolidine, 1-(2-(N-methylamino)ethyl)pyrrolidine),1-(3-aminopropyl)pyrrolidine, 1-(3-(N-methylamino)propyl)pyrrolidine),1-(2-aminoethyl)piperidine, 1-(2-(N-methylamino)ethyl)piperidine),1-(3-aminopropyl)piperidine, 1-(3-(N-methylamino)propyl)piperidine),4-(2-aminoethyl)morpholine, 4-(2-(methylamino)ethyl)morpholine),4-(3-aminopropyl)morpholine, 4-(3-(N-methylamino)propyl)morpholine),1-(2-aminoethyl)-4-methylpiperazine,1-(3-aminopropyl)-4-methylpiperazine,1-(3-(N-methylamino)propyl)-4-methylpiperazine,1-amino-4-methylpiperidine, 1-methylamino-4-methylpiperidine,1-ethyl-4-(N-methylamino)piperidine, 1-methylamino-4-propylpiperidine,1-butyl-4-(N-methylamino)piperidine, 1-(N,N-dimethylamino)piperidine,1-(N,N-diethylamino)piperidine, 4-(pyrrolidin-1-yl)piperidine,4-(piperidin-1-yl)piperidine, 3-aminoquinuclidine,3-(N-methylamino)quinuclidine, aniline, N-methylaniline,N,N-dimethyl-p-phenylenediamine, N,N-dimethyl-m-phenylenediamine,N,N,N′-trimethyl-p-phenylenediamine,N,N,N′-trimethyl-m-phenylenediamine, 1-naphthylamine, 2-naphthylamine,benzylamine, N-methylbenzylamine, phenethylamine,N-methylphenethylamine, 2-picolylamine, 3-picolylamine, 4-picolylamine,N-methyl-2-picolylamine, N-methyl-3-picolylamine,N-methyl-4-picolylamine, 2,5-diazabicyclo[2.2.1]heptane,2-methyl-2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octaneand 1,4-diazabicyclo[4.3.0]nonane.

Examples of the base are the above-mentioned organic bases and inorganicbases, of which, for example, diisopropylethylamine,dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodiumhydride is preferably used. The solvent used in the reaction is notspecifically limited, but a solvent that does not easily react with astarting material is desirable. Examples of such solvents are theabove-mentioned inert solvents, of which, for example, tetrahydrofuran,dichloromethane or N,N-dimethylformamide is preferably used. The amountsof the amine and base used in the reaction are 1 to 10 equivalents and 2to 20 equivalents, and preferably 1.5 to 5 equivalents and 2 to 10equivalents, respectively, to the compound of the formula (IIIA). Thereaction time is 10 minutes to 30 hours and is preferably 1 to 2 hours.The reaction temperature is a temperature of −78° C. to heating underreflux and is preferably −10° C. to 50° C.

The compound of the formula (IVA) can also be prepared by treating thecompound of the formula (IIA) with an isocyanate in an inert solvent inthe presence of a base and/or cuprous chloride. The isocyanate is notspecifically limited and includes, for example, ethyl isocyanate, methylisocyanate and phenyl isocyanate. Examples of the base are theabove-mentioned organic bases and inorganic bases, of which, forexample, diisopropylethylamine, dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine or sodium hydride is preferably used. The solventused in the reaction is not specifically limited, but a solvent thatdoes not easily react with a starting material is desirable. Examples ofsuch solvents are the above-mentioned inert solvents, of which, forexample, tetrahydrofuran, dichloromethane or N,N-dimethylformamide ispreferably used. The amounts of the base and isocyanate used in thereaction are 3 to 100 equivalents and 1 to 20 equivalents, preferably 5to 20 equivalents and 3 to 10 equivalents, respectively, to the compoundof the formula (IIIA). In the case where cuprous chloride is used, theamount thereof is 1 to 10 equivalents and preferably 2 to 6 equivalents.The reaction time is 10 minutes to 30 hours and is preferably 1 to 2hours. The reaction temperature is a temperature of −78° C. to heatingunder reflux and is preferably −10° C. to 50° C.

The hydroxyl compound in which one to three of OR^(3A), OR^(6A),OR^(16A) and OR^(21A) have not been protected in the step A1 can beconverted into a derivative having a plurality of urethane structures byconverting those hydroxyl groups into carbonic ester groups in the stepA3 and further converting them into carbamoyloxy groups in the step A4.

The step A5 is a step for producing the compound of the formula (VA).This step is carried out by subjecting the urethane derivative of theformula (IVA) to a deprotection treatment mentioned below in an inertsolvent. The deprotection reaction for the protecting groups of thehydroxyl groups varies depending on the type of the protecting group butis carried out by a method well known in organic synthetic chemistry.

For the respective hydroxyl group protected by, for example,1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or4-methoxytetrahydrothiopyranyl-S,S-dioxide, the deprotection reactioncan be easily carried out by treatment with an acid in an inert solvent.Examples of the acid are the above-mentioned organic acids and inorganicacid, of which, for example, pyridinium p-toluenesulfonate,p-toluenesulfonic acid or camphorsulfonic acid is preferred. The solventused in the reaction is not specifically limited, but a solvent thatdoes not easily react with a starting material is desirable. Preferredexamples thereof are an alcohol solvent such as methanol, ethanol,isopropanol or tert-butanol, or a mixture of the alcohol and theabove-mentioned inert solvent. The amount of the acid used in thereaction is 0.5 to 5 equivalents and is preferably 1 to 3 equivalents tothe compound of the formula (IVA). The reaction time is 10 minutes to 10days and is preferably 1 day to 4 days. The reaction temperature is atemperature of −78° C. to heating under reflux and is preferably −10° C.to 50° C.

When the hydroxyl group is protected by the other protecting group suchas tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl,trimethylsilyl, triisopropylsilyl, di-tert-butylmethylsilyl ordiphenylmethylsilyl, it can be deprotected by the treatment of afluoride anion or an acid. Examples of the fluoride anion aretetrabutylammonium fluoride, hydrogen fluoride, potassium fluoride andhydrogen fluoride-pyridine. Examples of the acid are the above-mentionedorganic acids and inorganic acids, of which a preferred example isacetic acid, formic acid, trifluoroacetic acid, pyridiniump-toluenesulfonate or camphorsulfonic acid. The solvent used in thereaction is not specifically limited, but a solvent that does not easilyreact with a starting material is desirable. Examples thereof are theabove-mentioned inert solvents, of which, for example, tetrahydrofuran,diethyl ether or water is preferably used. The amounts of the fluorideanion and acid used in the reaction are 1 to 5 equivalents and 0.5 to 5equivalents, preferably 1 to 4 equivalents and 0.5 to 3 equivalents,respectively, to the compound of the formula (IVA). The reaction time is10 minutes to 30 hours and is preferably 1 to 2 hours. The reactiontemperature is a temperature of −78° C. to heating under reflux and ispreferably −10° C. to 50° C.

By a combination of the various protection methods for hydroxyl groupsdescribed in the step A1 and the various deprotection methods describedin the step A5, the respective hydroxyl groups at the 3-position,6-position and 21-position can be converted into urethane derivativesselectively. For example, a urethane derivative having a hydroxyl groupat the 6-position can be synthesized by subjecting the hydroxyl group atthe 6-position of the compound (IA) in which R^(3A), R^(16A) and R^(21A)are triethylsilyl groups to the step A3, the step A4 and the step A5sequentially.

The selective modification of the hydroxyl group at the 3-position,6-position or 21-position which is carried out by a combination of theprotection and the deprotection procedures can also be applied to theother modification methods described below.

B. A Preparation for a Thiourethane Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; R^(3E), R^(6E), R^(16E) and R^(21E) eachrepresents a hydrogen atom, a protecting group or a group represented bythe formula R^(N1)R^(N2) N—CS— (wherein R^(N1) and R^(N2) eachrepresents the same group as defined above), provided that R^(3E),R^(6E), R^(16E) and R^(21E) do not concurrently represent hydrogenatoms; and R^(3F), R^(6F), R^(16F) and R^(21F) each represents hydrogenatom or a group represented by the formula R^(N1)R^(N2)N—CS— (whereinR^(N1) and R^(N)2 each represents the same group as defined above).

The step B1 is a step for preparing the compound of the formula (IB) byusing a thioisocyanate or a thiocarbamoyl chloride instead of theisocyanate. This step is carried out by treating the compound of theformula (IIA) with an isothiocyanate or a thiocarbamoyl chloride in aninert solvent in the presence of a base or bis(tributyltin)oxide. Theisothiocyanate used herein is not specifically limited and includes, forexample, ethyl isothiocyanate, methyl isothiocyanate, phenylisothiocyanate, benzyl isothiocyanate, allyl isothiocyanate,2-(N,N-dimethylamino)ethyl isothiocyanate, 2-(N,N-diethylamino)ethylisothiocyanate, 3-(N,N-dimethylamino)propyl isothiocyanate,3-(N,N-diethylamino)propyl isothiocyanate, 2-(morpholin-4-yl)ethylisothiocyanate, 2-(piperidin-1-yl)ethyl isothiocyanate and2-(pyrrolidin-1-yl)ethyl isothiocyanate. The thiocarbamoyl chloride usedherein is not specifically limited and includes, for example,N,N-dimethylthiocarbamoyl chloride, N-phenyl-N-methylthiocarbamoylchloride, (morpholin-4-yl)thiocarbamoyl chloride,(4-methylpiperazin-1-yl)thiocarbamoyl chloride and(4-methylhomopiperazin-1-yl)thiocarbamoyl chloride. Examples of the baseare the above-mentioned organic bases and inorganic bases, of which, forexample, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine or sodium hydride is preferably used. The solventused in the reaction is not specifically limited, but a solvent thatdoes not easily react with a starting material is desirable. Examples ofsuch solvents are the above-mentioned inert solvents, of which, forexample, tetrahydrofuran, dichloromethane, N,N-dimethylformamide ortoluene is preferably used. The amounts of the base orbis(tributyltin)oxide, and isothiocyanate or thiocarbamoyl chloride are1 to 5 equivalents and 1 to 10 equivalents, preferably 1 to 3equivalents and 2 to 5 equivalents, respectively, to the compound of theformula (IIA). The reaction time is 10 minutes to 72 hours and ispreferably 1 to 24 hours. The reaction temperature is a temperature of−78° C. to heating under reflux and is preferably −10° C. to 70° C.

A compound of the formula (IB) having a plurality of thiocarbamoylgroups can be synthesized by converting the hydroxyl group(s) of thecompound represented by the formula (IIA), in which one to three ofOR^(3A), OR^(6A), OR^(16A) and OR^(21A) are not protected, intothiocarbamoyloxy group(s) in the step B1.

The thiourethane derivative of the formula (IIB) can be synthesized bydeprotecting the protecting group of the hydroxyl group by the step A5.

C. A Preparation for an Ether Derivative

In the formula, R^(3G), R^(6G), R^(16G) and R^(21G) each represents ahydrogen atom or a protecting group, provided that R^(3G), R^(6G),R^(16G) and R^(21G) do not concurrently represent hydrogen atoms and atleast one of them represents a hydrogen atom; and R^(3H), R^(6H),R^(16H) and R^(21H) each represents a protecting group or an optionallysubstituted C₁₋₂₂ alkyl group.

The step C1 is a step for synthesizing the compound of the formula (IC).This step is carried out by the same way as in the reactioncorresponding to the step A1 of the preparation A, except that one tothree hydroxyl groups are to be protected.

On this step, alternatively, a compound in which one at the 3-position,6-position or 21-position is a hydroxyl group and the other hydroxylgroups are protected can be synthesized by using a combination of thevarious protection methods for the hydroxyl group corresponding to thestep A1 and deprotection methods for a protected hydroxyl groupcorresponding to the step A5 in the preparation.

The step C2 is a step for synthesizing the compound of the formula(IIC). This step is carried out by alkylating the unprotected hydroxylgroup(s) of the compound (IC).

The alkylation can be carried out by the treatment of an alkylatingagent of the formula R^(m)—X in the presence of a base. The substituentR^(m) represents a C₁₋₂₂ alkyl group which may have substituents andincludes, for example, methyl group, ethyl group and benzyl group. Xrepresents a leaving group. Examples of the leaving group are chlorogroup, bromo group, iodo group and trifluoromethanesulfonyl group.Examples of the base are the above-mentioned organic bases and inorganicbases, of which preferred examples are sodium hydride, lithiumbis(trimethylsilyl)amide, lithium diisopropylamide, lithiumdicyclohexylamide, potassium carbonate, cesium carbonate and1,8-bis(N,N-dimethylamino)naphthalene. The solvent used in the reactionis not specifically limited, but a solvent that does not easily reactwith a starting material is desirable. Examples thereof are theabove-mentioned inert solvents, of which, for example, diethyl ether,tetrahydrofuran, dimethoxyethane or toluene is preferably used. Theamounts of the alkylating agent and base used in the reaction are 3 to20 equivalents and 5 to 30 equivalents, preferably 3 to 5 equivalentsand 5 to 10 equivalents, respectively, to the compound of the formula(IC). The reaction time is 10 minutes to 48 hours and is preferably 1 to24 hours. The reaction temperature is a temperature of −78° C. toheating under reflux and is preferably −10° C. to 70° C.

In the formula, R^(3J), R^(6J), R^(16J) and R^(21J) each represents analkyl group or a protecting group; R^(3K), R^(6K), R^(16K) and R^(21K)each represents an alkyl group or a hydrogen atom; and R^(7K) representsa carbamoyl group or a thiocarbamoyl group, and each may havesubstituents on the nitrogen atom.

If desired, a derivative having a carbamoyl group introduced into thehydroxyl group at the 7-position and an alkyl group introduced into oneor two of the hydroxyl groups at the 3-position, 6-position and21-position can be obtained by further subjecting the compound of theformula (IIC) to the steps A2, A3, A4 and A5.

Alternatively, a derivative having a thiocarbamoyl group introduced intothe hydroxyl group at the 7-position and an alkyl group introduced intoone or two of the hydroxyl groups at the 3-position, 6-position and21-position can be obtained by subjecting the compound of the formula(IIIC) to the step B1 and then to the step A5.

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; and R^(3L), R^(6L), R^(7L), R^(16L) andR^(21L) each represents a hydrogen atom or an alkyl group.

The ether derivative represented by the formula (IIC′), in which thehydroxyl group at the 7-position is alkylated can be prepared bysubjecting the compound of the formula (IIA) to the step C2 and then tothe step A5 in a similar way as described above.

Further, a corresponding ether derivative can be prepared by using,instead of the alkylating agent, an unsaturated-alkylating agent,aralkylating agent or heteroaralkylating agent that can prepare adesired compound of the formula (I).

D. A Preparation for an Ester Derivative

In the formula, R^(3G), R^(6G), R^(16G) and R^(21G) each represents thesame group as defined above; and R^(3M), R^(6M), R^(16M) and R^(21M)each represents a hydrogen atom, a protecting group or a grouprepresented by the formula R^(co)CO— (wherein R^(co) represents ahydrogen atom, an optionally substituted C₁₋₂₂ alkyl group, anoptionally substituted unsaturated C₂-C₂₂ alkyl group, an optionallysubstituted C₆₋₁₄ aryl group, an optionally substituted 5 to 14-memberedheteroaryl group, an optionally substituted C₇₋₂₂ aralkyl group or anoptionally substituted 5 to 14-membered heteroaralkyl group), providedthat R^(3M), R^(6M), R^(16M) and R^(21M) do not concurrently representhydrogen atoms.

The step D1 is a step for converting the unprotected hydroxyl group intoan ester group by using the compound of the formula (IC) synthesized inthe step C1 as a starting material.

The esterification is carried out, for example, by using an acidanhydride with a base, an acid halide with a base, a carboxylic acidwith a condensing agent or by carrying out Mitsunobu reaction. As theacid anhydride, a variety of anhydrides of carboxylic acids are used.Examples thereof are a mixed anhydride comprising, for example, aceticacid, propionic acid, butyric acid, valeric acid and benzoic acid; asymmetrical anhydride; a cyclic anhydride such as succinic anhydride,glutaric anhydride or adipic anhydride. Preferred examples are aceticanhydride, propionic anhydride, butyric anhydride and benzoic anhydride.As the acid halide, for example, various acid chlorides and bromides areused, of which a preferred example is acetyl chloride, propionylchloride, benzoyl chloride or benzoyl bromide. Examples of the base arethe above-mentioned organic bases and inorganic bases, of which apreferred example is imidazole, 4-dimethylaminopyridine, pyridine orsodium hydride. As the carboxylic acid, various carboxylic acids areused, of which a preferred example is acetic acid or propionic acid.Preferred examples of the condensing agent are, for example,dicyclohexylcarbodiimide, trifluoroacetic anhydride,carbonyldiimidazole, N,N-diisopropylcarbodiimide and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In the Mitsunobureaction, a variety of carboxylic acids can be substituted in thepresence of triphenylphosphine and diethyl azodicarboxylate ordiisopropyl azodicarboxylate. The solvent used in each of the reactionsis not specifically limited, but a solvent that does not easily reactwith a starting material is desirable. Examples thereof are theabove-mentioned inert solvents, of which, for example, dichloromethane,chloroform or tetrahydrofuran is preferably used. The amounts of theacid anhydride with the base, the acid halide with the base, and thecarboxylic acid with the condensing agent are 1 to 10 equivalents with 3to 20 equivalents, 1 to 10 equivalents with 3 to 20 equivalents, and 1to 20 equivalents with 1 to 20 equivalents, preferably 1 to 5equivalents with 2 to 10 equivalents, 1 to 5 equivalents with 2 to 10equivalents, and 1 to 5 equivalents with 1 to 5 equivalents,respectively, to the compound of the formula (IC). The reaction can beaccelerated by adding 0.2 to 2 equivalents of 4-dimethylaminopyridine asthe case requires. The reaction time is 10 minutes to 30 hours and ispreferably 1 to 2 hours. The reaction temperature is a temperature of−78° C. to heating under reflux and is preferably −10° C. to 50° C.

The compound of the formula (ID) can be produced by subjecting thethus-synthesized ester derivative to a reaction similar to the step A5to thereby deprotect the protecting group of a hydroxyl group.

It is also possible to esterify one to four hydroxyl groups by carryingout an esterification similar to the step D1 using 11107D as a startingmaterial.

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; and R^(3N), R^(6N), R^(7N), R^(16N) orR^(21N) represents a hydrogen atom or a group represented by the formulaR^(co)CO— (wherein R^(co) represents the same group as defined above).

The derivative represented by the formula (ID′) in which the hydroxylgroup at the 7-position is esterified can be synthesized by subjectingthe compound of the formula (IIA) to the step D1 and then to the step A5in a similar way as described above.

E. A Preparation for a Phosphoric Ester or Amidophosphoric EsterDerivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; R^(3P), R^(6P), R^(7P), R^(6P) and R^(21P)each represents a hydrogen atom, a group represented by the formula(R^(N3)O)₂PO—, the formula (R^(N1)R^(N2)N)₂PO— or the formula(R^(N1)R^(N2)N)(R^(N3)O)PO— (wherein R^(N1), R^(N2) and R^(N3) eachrepresents the same group as defined above).

The step E1 is a step for converting the hydroxyl group of the compoundof the formula (IIA) as a starting material into a phosphoric ester oran amidophosphoric ester.

The phosphoric-esterification is carried out, for example, by using aphosphoryl halide and a base. Various phosphoryl halides can be usedherein, and examples thereof are a dialkoxyphosphoryl chloride, adiphenyloxyphosphoryl chloride, an alkoxy(N,N-disubstitutedamino)phosphoryl chloride, an allyloxy(N,N-disubstitutedamino)phosphoryl chloride, an alkoxy(N-substituted amino)phosphorylchloride and an allyloxy(N-substituted amino)phosphoryl chloride.Examples of the base are the above-mentioned organic bases and inorganicbases, of which a preferred example is pyridine,4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodiumhydride, n-butyllithium, potassium carbonate or sodium carbonate. Thesolvent used in each of the reactions is not specifically limited, but asolvent that does not easily react with a starting material isdesirable. Examples thereof are the above-mentioned inert solvents, ofwhich, for example, dichloromethane, chloroform, tetrahydrofuran orN,N-dimethylformamide is preferably used. The reaction time is 10minutes to 72 hours and is preferably 1 to 24 hours. The amounts of thephosphoryl halide and base used in the reaction are 1 to 10 equivalentsand 2 to 20 equivalents, preferably 1 to 5 equivalents and 2 to 10equivalents, respectively, to the compound of the formula (IIA). Thereaction temperature is a temperature of −78° C. to heating under refluxand is preferably −10° C. to 50° C.

The compound of the formula (IE) can be prepared by subjecting thethus-synthesized phosphoric ester derivative to a similar reaction asthe step A5 to thereby deprotect the protecting group of a hydroxylgroup.

It is also possible to convert one to four hydroxyl groups intophosphoric esters by carrying out phosphoric-esterification of 11107D asa starting material by a similar way as described for the step E1.

F. A Preparation for a Sulfuric Ester or Amidosulfuric Ester Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; and R^(3Q), R^(6Q), R^(7Q), R^(16Q) andR^(21Q) each represents a hydrogen atom or a group represented byR^(N1)R^(N2)N—SO₂— or R^(N3)O—SO₂— (wherein R^(N1), R^(N2) and R^(N3)each represents the same group as defined above).

The step F1 is a step for converting the hydroxyl group of the compoundof the formula (IIA) as a starting material into a sulfuric ester.

The sulfuric-esterification is carried out, for example, by using asulfonyl halide and a base. Various sulfonyl halides can be used herein,and examples thereof are an alkoxysulfonyl chloride and anN,N-disubstituted sulfamoyl chloride. Examples of the base are theabove-mentioned organic bases and inorganic bases, of which a preferredexample is pyridine, 4-dimethylaminopyridine, triethylamine,ethyldiisopropylamine, sodium hydride, n-butyllithium, potassiumcarbonate or sodium carbonate. The solvent used in each of the reactionsis not specifically limited, but a solvent that does not easily reactwith a starting material is desirable. Examples thereof are theabove-mentioned inert solvents, of which, for example, dichloromethane,chloroform, tetrahydrofuran or N,N-dimethylformamide is preferably used.The amounts of the sulfonyl halide and base used in the reaction are 1to 10 equivalents and 2 to 20 equivalents, preferably 1 to 5 equivalentsand 2 to 10 equivalents, respectively, to the compounds of the formula(IIA). The reaction time is 10 minutes to 72 hours and is preferably 1to 24 hours. The reaction temperature is a temperature of −78° C. toheating under reflux and is preferably −10° C. to 50° C.

The compound of the formula (IF) can be synthesized by subjecting thethose synthesized sulfuric ester derivative to a similar reaction as thestep A5 to thereby deprotect the hydroxyl-protecting group.

It is also possible to convert one to four of the hydroxyl groups intosulfuric acid esters by subjecting 11107D as a starting material tosulfuric-esterification by a similar way as the step F1.

G. A Preparation for a Halogen Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; R^(3R), R^(6R), R^(16R) and R^(21R) eachrepresents a hydroxyl group or a halogen atom.

The step G1 is a step for converting the hydroxyl group of the compoundof the formula (IA) as a starting material into a halogen.

The halogenation is carried out, for example, by treatingdiethylaminosulfur trifluoride (DAST) or triphenylphosphine with carbontetrabromide, bromine, phosphorus tribromide, iodine or carbontetrachloride in the presence of a base. The base used herein includes,for example, general organic bases and inorganic bases such asdiisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine,2,6-lutidine and sodium hydride. The solvent used in the reaction is notspecifically limited, but a solvent that does not easily react with astarting material is desirable. Examples thereof are tetrahydrofuran,dichloromethane and N,N-dimethylformamide. Among them, fluorination withdiethylaminosulfur trifluoride is preferred. The amount ofdiethylaminosulfur trifluoride (DAST) is 1 to 5 equivalents, andpreferably 1 to 3 equivalents to the compound of the formula (IIA). Thereaction time is 10 minutes to 10 hours. The reaction temperature is atemperature of −78° C. to room temperature.

The compound of the formula (IG) can be synthesized by subjecting thethose synthesized halogen derivative to the procedure of the step A5 tothereby remove the protecting group of a hydroxyl group.

H. A Preparation for a Sulfonic Ester Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; and R^(3S), R^(6S), R^(7S), R^(16S) andR^(21S) each represents a hydrogen atom or a group represented byR^(N3)SO₂— (wherein R^(N3) represents the same group as defined above).

The step H1 is a step for sulfonylating the hydroxyl group of thecompound of the formula (IIA) as a starting material.

The sulfonylation can be carried out, for example, by the treatment of asulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfonylchloride or benzenesulfonyl chloride in the presence of a base. Examplesof the base are general organic bases and inorganic bases such asdiisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine,2,6-lutidine and sodium hydride. The solvent used in the reaction is notspecifically limited, but a solvent that does not easily react with astarting material is desirable. Examples thereof are tetrahydrofuran,dichloromethane and N,N-dimethylformamide. The amounts of the sulfonylchloride and base used in the reaction are 1 to 5 equivalents and 2 to10 equivalents, preferably 1 to 3 equivalents and 2 to 6 equivalents,respectively, to the compound of the formula (IIA). The reaction time is10 minutes to 30 hours. The reaction temperature is a temperature of−78° C. to heating under reflux.

The derivative represented by the formula (IH) in which the hydroxylgroup at the 7-position is sulfonylated can be synthesized by subjectingthe those synthesized sulfonic ester derivative to the step A5 todeprotect the protecting group of a hydroxyl group.

It is also possible that 11107D as a starting material is subjected tosulfonylation by a similar procedure as the step H1 to therebysulfonylate one to four of the hydroxyl groups.

I. A Preparation for an Amine Derivative

In the formula, R^(3A), R^(6A), R^(16A) and R^(21A) each represents thesame group as defined above; and R^(3T), R^(6T), R^(7T), R^(16T) andR^(21T) each represents a hydroxyl group or the formula R^(N1)R^(N2)N—(wherein R^(N1) and R^(N2) each represents the same group as definedabove).

The step I1 is a step for converting the hydroxyl group of the compoundof (IIA) directly into an amine or into a good leaving group, then intoan azide and then into an amine by reduction.

In the case where the hydroxyl group is converted into an azide,examples of reagents used in the reaction are 1) diphenylphosphorylazide (DPPA), diethyl azodicarboxylate and triphenylphosphine, 2) DPPAand 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 3) hydrogen azide, diethylazodicarboxylate and triphenylphosphine, 4) DPPA,tetramethylazodicarboxamide (TMAD) and tributylphosphine, and 5) sodiumazide in the presence of a base. Examples of the base are theabove-mentioned organic bases and inorganic bases, of which, forexample, diisopropylethylamine, dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine or sodium hydride is preferably used. It is alsopossible to convert into an azide by the treatment of sodium azide inthe presence of a palladium catalyst. An example of the palladiumcatalyst is Pd(PPh₃)₄. The solvent used in the reaction is notspecifically limited, but a solvent that does not easily react with astarting material is desirable. Examples thereof are tetrahydrofuran,dichloromethane, N,N-dimethylformamide, toluene and benzene. Thereaction time is 10 minutes to 30 hours. The reaction temperature is atemperature of −78° C. to heating under reflux.

The reduction from the azide to the amine can be carried out by using,for example, triphenylphosphine or lithium aluminum hydride. The azidecan be also reduced into the amine, for example, by using a catalystsuch as palladium-carbon or Lindlar catalyst under hydrogen atmosphere.The solvent used in the reaction is not specifically limited, but asolvent that does not easily react with a starting material isdesirable. Examples thereof are tetrahydrofuran, diethyl ether andethanol. The reaction time is 10 minutes to 30 hours. The reactiontemperature is a temperature of −78° C. to heating under reflux.

The conversion of a hydroxyl group into a good leaving group can becarried out by the similar procedure of the step G1 (halogenation) orthe step H1 (sulfonylation). Examples of the good leaving group arechloro group, bromo group, iodo group, methanesulfonyl group andp-toluenesulfonyl group. Next, by treating the converted compound havinga leaving group with an amine in an inert solvent in the presence of abase, the compound in which the hydroxyl group is converted into anamino group or substituted amino group can be synthesized.

Examples of the amine used herein are methylamine, ethylamine,dimethylamine and diethylamine. Examples of the base are theabove-mentioned organic bases and inorganic bases, of which, forexample, diisopropylethylamine, dimethylaminopyridine, triethylamine,pyridine, 2,6-lutidine or sodium hydride is preferably used. The solventused in the reaction is not specifically limited, but a solvent thatdoes not easily react with a starting material is desirable. Examplesthereof are the above-mentioned inert solvents, of which, for example,tetrahydrofuran, dichloromethane or N,N-dimethylformamide is preferablyused. The reaction time is 10 minutes to 30 hours and is preferably 1 to2 hours. The reaction temperature is a temperature of −78° C. to heatingunder reflux and is preferably −10° C. to 50° C.

The compound of the formula (II) can be prepared by subjecting the thosesynthesized amine derivative to deprotect the protecting group of ahydroxyl group the by a similar way as the step A5. It is also possibleto convert one or two of the hydroxyl groups of 11107D as a startingmaterial into amino groups by amination by a similar way as the step I1.

The compound of the formula (I) can be also prepared by alkylating,acylating, carbamoylating or sulfonylating the amino group of thecompound of the formula (II) by methods well known in organic syntheticchemistry and the above-mentioned methods.

J. A Preparation for an Oxo-Compound (Oxidation of a Hydroxyl Group)

In the formula, either one of R^(3Ja) and R^(3Ja) represents a hydroxylgroup and the other represents a hydrogen atom, or R^(3Ja) and R^(3Ja)together with the carbon atom to which R^(3Ja) and R^(3Ja) are boundrepresent an oxo group, either one of R^(21Ja) and R^(21Ja) represents ahydroxyl group and the other represents a hydrogen atom, or R^(21Ja) andR^(21Ja) together with the carbon atom to which R^(21Ja) and R^(21Ja)are bound represent an oxo group.

The step J1 is a step for synthesizing the oxo-compound represented bythe formula (IIJ) by oxidizing the hydroxyl group of 11107D as astarting material.

Examples of the oxidizing agent used in this step are manganese dioxide,pyridinium chlorochromate, pyridinium dichromate, Dess-Martin reagentand reagents used in Swern oxidation. The solvent used in the reactionis not specifically limited, but a solvent that does not easily reactwith a starting material is desirable. Examples thereof aretetrahydrofuran, dichloromethane, chloroform and toluene. The reactiontemperature is a temperature of −78° C. to heating under reflux. Thereaction time is 10 minutes to 78 hours. Among these reactions, forexample, the reaction using Dess-Martin reagent, manganese dioxide orreagents used in Swern oxidation is preferred, of which the reactionusing a Dess-Martin reagent is typically preferred. As the solvent foruse in the oxidation using Dess-Martin reagent, dichloromethane orchloroform is typically preferred. The amount of the oxidizing agentused herein is 1 to 20 equivalents and is preferably 1 to 5 equivalentsto the compound (11107D). The reaction temperature is preferably 0° C.to room temperature. The reaction time is 30 minutes to 24 hours and ispreferably 1 to 8 hours.

A compound in which the hydroxyl group at the 3-position or 21-positionof these derivatives has been converted into an oxo moiety can besynthesized by subjecting, for example, an urethane derivative,thiourethane derivative, ester derivative or alkyl derivative, which isprecedently prepared by the above-mentioned methods to the step J1instead of 11107D. Further, a 7-oxo compound can be obtained byoxidizing the hydroxyl group at the 7-position of the compoundrepresented by the formula (IIA).

Further, the hydroxyl group at the 3-position, 7-position and/or21-position can be selectively converted into an oxo moiety by a variouscombination of the protection and deprotection conditions of the step A1and the step A5 with the step J1. In addition, a compound which has bothan oxo moiety and a urethane, thiourethane, ester or alkyl moiety can berespectively synthesized by subjecting a compound, which is precedentlyconverted into an oxo moiety, to the above-mentioned methods for aurethane derivative, thiourethane derivative, ester derivative or alkylderivative.

The compounds represented by the formula (I) can be synthesized by anappropriate combination of the reactions A to J and protection anddeprotection procedures of the hydroxyl group.

After termination of the reaction, the target product in the respectivereaction is isolated from a reaction mixture according to a conventionalprocedure. For example, the target compound can be obtained byfiltration, if insoluble matter is present, and evaporation of thesolvent, or by diluting the reaction mixture with an organic solventsuch as ethyl acetate, washing the organic layer with water, drying overanhydrous magnesium sulfate and evaporating the solvent. The compoundcan be further purified by a conventional procedure such as columnchromatography, thin layer chromatography or high performance liquidchromatography as the case requires.

To illustrate the usefulness of the present invention specifically, theVEGF transcription-suppressing activity, growth inhibitory activity onWiDr human colon cancer cell, growth inhibitory activity on solidcancer, body weight loss (acute toxicity) and stability in an aqueoussolution of representative compounds of the compounds of the formula (I)according to the present invention were determined.

TEST EXAMPLE 1 CONSTRUCTION OF REPORTER SYSTEM FOR SCREENING COMPOUNDWHICH SUPPRESSES THE TRANSCRIPTION OF VEGF

In order to prepare reporter system reflecting transcription from VEGFpromoter, VEGF promoter sequence was cloned, and inserted in secretoryalkaline phosphatase (PLAP) vector to construct reporter vector.

In order to obtain the promoter region of human VEGF, VEGF genomic DNAwas cloned from phage library. PCR primers having the sequencesdescribed in Sequence Numbers 1 and 2 were designed based on VEGF cDNA(GenBank accession number: X62568) and a fragment having about 340 bpwas obtained by carrying out PCR. Human genomic phage library (Humangenomic library, Clontech Co.) was screened using this as a probe toobtain VEGF genomic DNA. The DNA was digested by EcoRI, and theresultant fragments were inserted in the EcoRI site of pUC18. Finally,pUC18-VEGFA containing about 5.4 kb of VEGF 5′ flanking region wasobtained. The pUC18-VEGFA was digested by KpnI/NheI, VEGF promoterregion of about 2.3 kb obtained was inserted in the multi cloning siteKpnI/NheI of secretory alkaline phosphatase (PLAP) vector (Goto et al,Mol. Pharmacol., 49, 860-873, 1996), and thus, VEGF-PLAP vector wasconstructed.

The above-mentioned VEGF-PLAP vector was transfected in the U251 cellcultured in the DULBECCO-modified eagle medium (DMEM; manufactured bySIGMA Co., Ltd.) containing 10% fetal calf serum, and the cells werecultured in the presence of 1 mg/mL G418 (Merck Co.) to establish G418resistant stable clone (U251/1-8 cell).

It was confirmed that U251/1-8 cell secreted PLAP under hypoxiccondition (2% O₂ incubator) in the same manner as in the report (Cell.Mol. Biol. Res. 40, 35-39, 1994) and was a reporter system reflectingthe transcription from VEGF promoter. The screening of the compoundsuppressing VEGF production which was induced by hypoxic stimulation wascarried out below using the clone.

TEST EXAMPLE 2 VEGF TRANSCRIPTION-SUPPRESSING ACTIVITIES OF VARIOUS11107 ANALOGUES AND DERIVATIVES

In order to remove the influence of alkaline phosphates in serum,U251/1-8 cells were rinsed twice with the adequate amount of PBS(Phosphate buffered saline), diluted in the DMEM medium containing 10%of serum in which alkaline phosphates was inactivated by the treatmentof 65° C. for 20 min., and dispensed in 96-well plates by 4×10⁴cells/180 μL.

After culturing at 37° C. overnight in a CO₂ incubator (5% CO₂), 20 μLof the above-mentioned incubation solution containing the test compounddiluted with 3-fold succession was added, and then they were incubatedin a hypoxic (2% CO₂) incubator for 18 hours. With respect to the PLAPactivity in the culture supernatants, 10 μL of the supernatants wasadded to 50 μL of 0.28 M Na₂CO₃—NaHCO₃ buffer solution (pH 10.0, 8.0 mMMgSO₄), and finally 50 μL of alkaline phosphatase substrate (LUMISTEIN,Genomescience Co.) was added. After reacting for one hour, the alkalinephosphatase activity of the PLAP was measured by detecting the chemicalluminescence by a micro plate reader (Perkin-Elmer Co.). The PLAPactivity under normoxia was set as 0%, the PLAP activity of cell whichwas treated under hypoxia was set as 100%, and the concentrationsuppressing the PLAP activity by 50% was set as the IC₅₀ value of PLAP.The IC₅₀ values of 11107D derivatives shown in Examples were measured,and the IC₅₀ values of representative 11107D derivatives are shown inTable 1. The 11107D derivatives showed strong VEGFtranscription-suppressing activities.

TABLE 1 VEGF transcription-suppressing Compound activities (IC₅₀: nM) 632.0 9 12.9 12 10.2 16 3.1 17 3.9 21 6.1 22 25.6 24 5.5 25 2.9 26 2.8 273.7 44 3.9 45 1.9 75 9.1 95 1.2 109 3.3 122 4.4 127 2.4 131 1.7 136 1.2142 11.2

TEST EXAMPLE 3 GROWTH INHIBITORY ACTIVITIES ON WIDR HUMAN COLON CANCERCELLS

WiDr human colon cancer cells cultured in DULBECCO-modified eagle medium(DMEM; manufactured by SIGMA Co., Ltd.) containing 10% fetal calf serum,penicillin (100 unit/mL) and streptomycin (100 μg/mL) were dispensed in96-well plates by 2×10³ cells/well. After culturing overnight in a CO₂incubator, 20 μL of the above-mentioned incubation solution containingthe test compound diluted with 3-fold succession was added, followed byincubation. After three days, 50 μL of 3.3 mg/mL MTT solution was added,followed by culturing for further one hour. Then, formazan formed by thereduction by the action of living cells was extracted with 100 μL ofDMSO, the absorbance (A540/A660) was determined and was set as the indexof the number of living cells.

The concentrations of the compounds of the formula (I) at which thegrowth of WiDr human colon cancer cells are inhibited 50% weredetermined. The IC₅₀ values of representative compounds are shown inTable 2. The compounds of the formula (I) showed strong growthinhibitory activities on WiDr human colon cancer cells.

TABLE 2 Growth inhibitory activities on WiDr human colon cancer cellsCompound (IC₅₀: nM) 6 12.5 9 5.5 16 2.0 17 2.6 21 3.2 22 14.6 24 5.3 251.2 26 1.6 27 1.2 44 2.1 45 0.7 75 4.1 95 0.5 109 1.5 122 1.1 127 0.7131 0.7 136 0.8 142 4.9

TEST EXAMPLE 4 SOLID TUMOR GROWTH INHIBITORY ACTIVITIES

In order to study solid tumor growth inhibitory activities of thecompounds of the formula (I) in vivo, WiDr human colon cancer cells wereimplanted subcutaneously into the flanks of nude mice. transplanted tothe subcutaneous body sides of mice. The animals were grouped so thatthe average of the volumes of the respective groups became uniform, whenit reached about 100 mm³. Control group was made up of 10 mice and11107D-administering groups were made up of 5 mice. The derivatives wereadministered for the administering groups for 5 consecutive days byintravenous injection so as to be any of 0.625 mg, 1.25 mg, 2.5 mg, 5 mgand 10 mg/kg/day, and a vehicle was administered to the control group.The tumor volumes on Day 15 were measured, and relative tumor volumeratios (T/C %) were determined setting the tumor volume of the controlgroup as 100%. The T/C % of representative compounds of the formula (I)are shown in Table 3. The body weights on Day 1, Day 5, Day 8, Day 12and Day 15 (or 16) were measured, and relative body weight variationswere determined setting the body weight on Day 1 as 100%. The relativebody weight ratios on the day where the body weight reached the minimumwere defined as the minimum relative weight ratios and are shown inTable 3.

TABLE 3 Growth inhibitory activities the minimum Dose in the WiDr humansolid relative weight Compound (mg/kg) tumor model (T/C %) ratios 6 1.2535 0.81 9 5.0 10 0.86 12 2.5 21 0.85 15 2.5 36 0.82 16 2.5 28 0.90 212.5 28 0.80 22 5.0 39 0.74 26 2.5 42 0.93 44 5.0 19 0.89 45 5.0 20 0.9075 5.0 17 0.82 109 0.625 36 0.89 131 2.5 28 0.83

The compounds of the formula (I) showed growth inhibitory activities inthe WiDr human colon tumor model even in a dose without remarkableweight loss also in vivo.

TEST EXAMPLE 5 STABILITY IN AN AQUEOUS SOLUTION

The compounds of the formula (I) were dissolved in DMSO inconcentrations of 10 to 20 mM, and these were diluted about 500 foldswith Britton-Robinson's buffer solution of pH 7. Each of the solutionsas sample solutions was incubated at 25° C. for 24 hours.

The sample solutions were analyzed by high performance liquidchromatography before and after incubation, and the residual ratios ofthe tested substances in the sample solutions after incubation weredetermined from the peak areas of the obtained chromatograms.

Peak area (mAU × sec) The residual ratios Example initial after 24 hours(%) FD895 1197 993 83.0 11107D 3994 3817 95.6 Compound 9 5690 5476 96.2Compound 12 5450 5169 94.9 Compound 22 4713 4514 95.8 Compound 44 40313820 94.8 Compound 45 5291 5024 95.0 Compound 75 2594 2478 95.5 Compound109 2224 2111 94.9 Compound 122 4872 4620 94.8 Compound 130 4819 458395.1 Compound 131 168 157 93.2 Compound 136 3750 3579 95.4 Compound 1423916 3705 94.6

The results show that the content of FD895 decreased to 83% after 24hours, but that the contents of Compounds 9, 12 and 22 as representativecompounds of the compounds of the formula (I) remained 95 to 96%,indicating that the 11107D derivatives are stable in an aqueoussolution.

As is evident from the above Pharmacological Test Examples, thecompounds of the formula (I) according to the present inventionespecially suppress VEGF production by varying the gene expression andare expected to use as an antitumor agent, in particular, as a treatingagent for solid cancer, a carcinoma metastasis suppressor, as well as anagent for treating diabetic retinopathy, rheumatoid arthritis andanginoma. Further, as is evident from the toxicity test of Test Example4, the compounds of the formula (I) show growth inhibitory activities inthe WiDr human colon tumor model in such a dose as to not causeremarkable weight loss of the tested mice and are safe compounds.Accordingly, they are efficacious as an agent for preventing or treatinga disease against which gene expression control is efficacious, adisease against which VEGF production suppressing activity isefficacious and a disease against which angiogenesis inhibiting activityis efficacious. The “preventing or treating” indicates either ofpreventing or treating, or both of them. More specifically, thecompounds of the formula (I) of the present invention are effective asan antitumor agent, and in particular, as an antitumor agent and acarcinoma metastasis suppressor for solid cancer. As the solid cancer,for example, pancreatic cancer, gastric cancer, colon cancer, breastcancer, prostate cancer, lung cancer, kidney cancer, brain tumor, headand neck cancer, esophageal cancer, skin cancer, liver cancer, uteruscancer, cervix uteri cancer, urinary bladder cancer, thyroid cancer,testicular cancer, chorionic carcinoma, osteosarcoma, soft tissuesarcoma, and ovarian cancer may be proposed, of which a cancer such ascolon cancer, breast cancer, prostate cancer, lung cancer, head and neckcancer or ovarian cancer is preferred. Further, they are also effectiveas an antitumor agent for leukemia. Further, they are also effective asan agent for treating hematoma. Furthermore, they are also effective asan agent for treating diabetic retinopathy, rheumatoid arthritis andhematoma, which is based on VEGF production suppressing action. Inaddition, they are also effective as an agent for treating inflammatorydiseases consisting of osteoarthritis, psoriasis and prolongedhypersensitivity reaction, and atherosclerosis.

When the compounds are prepared as an injection, a pH regulator, abuffer, a stabilizer, a solubilizer and the like are added to the maindrug, if necessary, to prepare an subcutaneous, intramuscular,intra-articular or intravenous injection according to a conventionalprocedure.

When the compound is administered as a preventive or therapeutic agentfor various diseases, it may be orally administered as tablets, powders,granules, capsules, syrups and the like, and may be parenterally orparenterally administered as a spray, a suppository, an injection, anexternal preparation or a drip. The dose remarkably varies according tothe severity of symptom, age, the kind of liver disease etc., andapproximately 1 mg to 100 mg per day for an adult is administered ingeneral at one time or several times.

Conventional excipients are used at production of pharmaceuticals, andthe pharmaceutical products are prepared by a conventional method.Namely, when a solid formulation for oral use is prepared, a filler isadded to the main drug, and if necessary, a binder, a disintegrant, alubricant, a colorant, a flavoring agent and the like are added thereto,and then tablets, coated tablets, granules, powders, capsules and thelike are prepared. It is needless to say that sugar coating, gelatincoating or suitable coating may conducted on the tablet and granule, ifnecessary.

According to the present invention, the compounds of the formula (I) ofthe present invention suppress, in particular, VEGF production byvarying the gene expression and show excellent antitumor activities inin vivo solid tumor models. Further, the compounds of the formula (I) ofthe present invention are stable in an aqueous solution and can provide,for example, an agent for treating cancer, in particular, an agent fortreating solid cancer, a carcinoma metastasis suppressor, an agent fortreating diabetic retinopathy, rheumatoid arthritis and angioma.

EXAMPLES

The present invention will be illustrated in further detail withreference to Examples and Referential Examples below, which are notintended to limit the scope of the present invention.

The symbols used in the chemical structural formulae in Examples will beillustrated below.

DEIPS: diethylisopropylsilyl group

Et: ethyl group

EE: 1-ethoxyethyl group

Me: methyl group

TES: triethylsilyl group

Example 1 Fermentation of Mer-11107 Strain and Purification of 11107D

One loopful of the slant culture (ISP-2) of Mer-11107 strain wasinoculated into a 500 ml Erlenmeyer flask containing 50 mL of seedmedium (2% of glycerin, 2% of glucose, 2% of soybean meal (ESUSAN-MEATmanufactured by Ajinomoto Co. Ltd.), 0.5% of yeast extract, 0.25% ofsodium chloride, 0.32% of calcium carbonate, 0.0005% of copper sulfate,0.0005% of manganese chloride, 0.0005% of zinc sulfate, pH 7.4), and itwas cultured at 28° C. for three days on a shaker to give the first seedculture. The seed culture (0.6 mL) was inoculated into a 500 mLErlenmeyer flask containing 60 mL of the producing medium (5% of solublestarch, 0.5% of corn steep liquor, 0.5% of dry yeast, 0.5% of glutenmeal, 0.1% of calcium carbonate) and it was fermented at 28° C. for fourdays on a rotary shaker to give a fermentation cultured broth.

The cultured broth (10 L) was extracted with 1-butanol (10 L), then thusacquired butanol layer was evaporated to dryness to give 100 g of crudeactive fraction. The crude active fraction was applied on Sephadex LH-20(1500 mL; manufactured by Pharmacia Co. Ltd.), and eluted withtetrahydrofuran-methanol (1:1) as a solvent. An eluted fraction from 540mL to 660 mL was concentrated to dryness, to give a residue (660 mg).The resulting residue was dissolved in a mixture of ethyl acetate andmethanol (9:1; v/v) and subjected to silica gel column chromatography(WAKO GEL C-200, 50 g). The column was eluted with a mixture (2 L)consisting of n-hexane and ethyl acetate (1:9, v/v), the fractionseluted from 1440 mL to 1566 mL were collected, evaporated to give 15 mgof a crude active fraction.

The obtained crude active fraction was subjected to preparative highperformance liquid chromatography (HPLC) under the following preparativeHPLC condition (A), and the fractions eluted at the retention time of 17minutes were collected. After removing acetonitrile, the respectivefractions were desalted by HPLC under the following preparative HPLCcondition (B) to give 11107D (Retention time: 36 minutes, 1.8 mg).

Preparative HPLC Conditions A:

Column: YMC-PACK ODS-AM F20 mm×250 mm (manufactured by YMC Co.)

Flow rate: 10 ml/min.

Detection: 240 nm

Eluent: acetonitrile/0.15% aqueous potassium dihydrogenphosphate (pH3.5) (2:8 to 8:2, v/v, 0 to 50 min., linear gradient)

Preparative HPLC Conditions B:

Column: YMC-PACK ODS-AM F20 mm×250 mm (manufactured by YMC Co.)

Flow rate: 10 mL/min.

Detection: 240 nm

Eluent: methanol/water (2:8 to 10:0, v/v, 0 to 40 min., linear gradient)

Example 2 Physico-Chemical Properties of 11107D

The physico-chemical properties of 11107D are shown below. The structureof 11107D was determined as shown below.

1. Appearance: colorless powder

2. Molecular weight: 552, ESI-MS m/z 551 (M−H)⁻, 575 (M+Na)⁺

3. Molecular formula: C₃₀H₄₈O₉

4. Solubility: soluble in dimethyl sulfoxide, pyridine, methanol andacetone, and slightly soluble in water

5. Color reaction: positive for iodine and sulfuric acid

6. Ultraviolet absorption spectrum (methanol, maximum value) nm: 239(ε33100)

7. Infrared absorption spectrum (KBr) cm⁻¹: 3417, 2967, 1732, 1714,1455, 1372, 1248, 1176

8. ¹H-NMR spectrum (CD₃OD, 500 MHz): δ ppm (integral, multiplicity,coupling constant J (Hz)):

0.93 (3H, d, J=7.0 Hz), 0.95 (3H, d, J=6.8 Hz), 0.98 (3H, t, J=8.0 Hz),1.23 (3H, s), 1.30 (1H, m), 1.36-1.66 (9H, m), 1.70 (1H, dd, J=6.4, 14.2Hz), 1.82 (3H, d, J=1.0 Hz), 1.90 (1H, dd, J=6.4, 14.2 Hz), 2.10 (3H,s), 2.52 (2H, m), 2.62 (1H, m), 2.72 (1H, dd, J=2.4, 8.3 Hz), 2.94 (1H,dt, J=2.4, 5.7 Hz), 3.55 (1H, dt, J=8.3, 4.4 Hz), 3.82 (1H, m), 5.10(1H, d, J=9.8 Hz), 5.11 (1H, d, J=10.8 Hz), 5.60 (1H, dd, J=9.8, 15.2Hz), 5.74 (1H, dd, J=8.3, 15.2 Hz), 5.92 (1H, d, J=15.2 Hz), 6.18 (1H,d, J=10.8 Hz), 6.57 (1H, dd, J=10.8, 15.2 Hz)

9. ¹³ C-NMR Spectrum (CD₃ OD, 125 MHz): δ ppm (multiplicity):

10.52 (q), 10.82 (q), 11.98 (q), 16.84 (q), 21.07 (q), 24.21 (q), 28.62(t), 28.79 (q), 30.46 (t), 37.53 (t), 40.10 (t), 41.80 (d), 42.58 (d),45.97 (t), 55.99 (d), 62.53 (d), 70.42 (d), 73.09 (s), 74.11 (s), 75.30(d), 80.31 (d), 84.19 (d), 123.64 (d), 127.10 (d), 131.76 (d), 133.81(s), 141.61 (d), 143.22 (d), 171.75 (s), 172.18 (s)

Example 3(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 3)

Example 3-1(8E,12E,14E)-7-Acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Formula XV) and(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Formula XVI)

To a solution of(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(50 mg, 0.09 mmol) in dichloromethane (2.5 mL) were added ethyl vinylether (326 mg, 4.5 mmol) and pyridinium p-toluenesulfonate (6.8 mg, 27μmol) at room temperature, followed by stirring at the same temperaturefor 19 hours. The reaction mixture was diluted with ethyl acetate andwashed with a saturated aqueous solution of sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtrated and evaporated. The resulting residue was purified by silicagel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethylacetate:hexane=30:70) to give(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(60 mg, 79%) as a colorless oil (Formula XV). ESI-MS m/z 863 (M+Na)⁺.

Next,(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(6 mg, 9%) was obtained as a colorless oil (Formula XVI) from an elutedfraction of ethyl acetate:hexane=50:50.

ESI-MS m/z 791 (M+Na)⁺.

Example 3-2(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide

To a solution of(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(145 mg, 0.17 mmol) in methanol (2.5 mL) was added potassium carbonate(95 mg, 0.69 mmol) at room temperature, followed by stirring at the sametemperature for two hours and 30 minutes. The reaction mixture wasdiluted with ethyl acetate and then washed with brine. The organic layerwas dried over anhydrous magnesium sulfate, filtrated and evaporated.The resulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=40:60) to givethe title compound (128 mg, 93%) as a colorless oil. ESI-MS m/z 821(M+Na)⁺.

Example 3-3(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide

To a solution of(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(139 mg, 0.17 mmol) in dichloromethane (2.5 mL) were added triethylamine(88 mg, 0.87 mmol), N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and4-nitrophenyl chloroformate (105 mg, 0.52 mmol) under ice cooling,followed by stirring at room temperature under nitrogen atmosphere forone hour. The reaction mixture was diluted with ethyl acetate, and thenwashed with a saturated aqueous solution of sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtrated and evaporated. The resulting residue was purified by silicagel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethylacetate:hexane=20:80) to give the title compound (134 mg, 80%) as acolorless oil.

ESI-MS m/z 986 (M+Na)⁺.

Example 3-4(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide

To(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide(11.4 mg, 12 μmol) was added a solution of 4-(pyrrolidin-1-yl)piperidine(2.4 mg, 16 μmol) in tetrahydrofuran (0.5 mL) at room temperature. Tothe mixture was added triethylamine (2.3 mg, 24 μmol) at roomtemperature, followed by stirring at the same temperature for threehours. The reaction mixture was evaporated to give the compound (11 mg)as a crude product (a pale yellow oil).

Example 3-5(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 3)

To the crude product of(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(11 mg, 11 mol) was added a solution of pyridinium p-toluenesulfonate(11.4 mg, 45 μmol) in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room temperature. Tothe mixture was added molecular sieves 4 Å (10 mg), followed by stirringat room temperature for 18.5 hours. Additional pyridiniump-toluenesulfonate (11.4 mg, 45 μmol) was added, followed by stirring atroom temperature for 72 hours. The reaction mixture was evaporated, andthe resulting residue was diluted with ethyl acetate, and then washedwith a saturated aqueous solution of sodium bicarbonate and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtrated andevaporated. The resulting residue was purified by thin layerchromatography (Fuji Silysia, NH Silica gel Plate,methanol:dichloromethane=1:19) to give the title compound (2.88 mg, 35%,two steps) as a colorless oil.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.92 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.22-1.68 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.78-2.00 (9H, m), 2.48-2.62 (3H, m),2.67 (1H, dd, J=2.4, 8.0 Hz), 2.68-2.92 (9H, m), 3.46-3.54 (1H, m),3.72-3.82 (1H, m), 4.24-4.40 (1H, m), 4.92 (1H, d, J=10.8 Hz), 5.06 (1H,d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 14.8 Hz), 5.72 (1H, dd, J=9.2, 14.8Hz), 5.86 (1H, d, J=14.8 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 4(8E,12E,14E)-7-(N-Ethylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 4)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.10 (3H, t, J=7.6 Hz), 1.20(3H, s), 1.22-1.62 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J=6.6, 13.7 Hz),1.77 (3H, s), 1.86 (1H, dd, J=5.7, 13.7 Hz), 2.50-2.53 (2H, m),2.53-2.60 (1H, m), 2.67 (1H, dd, J=2.4, 7.6 Hz), 2.89 (1H, dt, J=2.0,6.0 Hz), 3.12 (2H, q, J=7.2 Hz), 3.49-3.54 (1H, m), 3.74-3.81 (1H, m),4.82-4.98 (1H, covered with H₂O), 5.06 (1H, d, J=10.8 Hz), 5.55 (1H, dd,J=9.6, 15.2 Hz), 5.69 (1H, dd, J=9.2, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 604(M+Na)⁺.

Example 5(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-(3-(morpholin-4-yl)propyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 5)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.20 (3H, s), 1.26-1.73 (10H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.4, 14.1 Hz), 2.35-2.60(9H, m), 2.67 (1H, dd, J=2.4, 7.6 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz),3.15 (2H, t, J=7.2 Hz), 3.48-3.54 (1H, m), 3.68 (4H, t, J=4.8 Hz),3.74-3.82 (1H, m), 4.82-4.98 (1H, covered with H₂O), 5.06 (1H, d, J=10.8Hz), 5.55 (1H, dd, J=10.0, 15.2 Hz), 5.69 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.4 Hz), 6.52 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 681 (M+H)⁺.

Example 6(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 6)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

1H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.22 (3H, s), 1.24-1.68 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.28 (6H,s), 2.45-2.62 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.86-2.99 (4H, m),3.49-3.56 (1H, m), 3.75-3.82 (1H, m), 4.92 (1H, d, J=10.0 Hz), 5.06 (1H,d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.6 Hz), 5.72 (1H, dd, J=9.6, 15.2Hz), 5.87 (1H, d, J=14.8 Hz), 6.14 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 639 (M+H)⁺.

Example 7(8E,12E,14E)-(7-N-(3-(N′,N′-Dimethylamino)propyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 7)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.24-1.75 (10H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.9, 13.7 Hz), 2.28 (6H,s), 2.37 (2H, t, J=7.6 Hz), 2.48-2.62 (5H, m), 2.67 (1H, dd, J=2.4, 7.6Hz), 2.86-2.99 (4H, m), 3.48-3.58 (1H, m), 3.74-3.82 (1H, m), 4.93 (1H,d, J=10.4 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz),5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.6 Hz), 6.13 (1H, d,J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 653 (M+H)⁺.

Example 8(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)carbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 8)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.22-1.68 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.7, 14.3 Hz), 2.29 (6H,s), 2.44-2.62 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.49-3.56 (1H, m), 3.74-3.82 (1H, m), 4.82-4.98 (1H,covered with H₂O peak), 5.06 (1H, d, J=10.8 Hz), 5.55 (1H, dd, J=10.4,15.2 Hz), 5.69 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=10.8 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 625(M+H)⁺.

Example 9(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 9)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.887 (3H, d, J=6.6 Hz), 0.894(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.23-1.27 (4H, m), 1.33 (3H,s), 1.33-1.68 (7H, m), 1.77 (3H, d, J=0.7 Hz), 1.82-1.91 (3H, m), 2.35(3H, s), 2.50-2.66 (7H, m), 2.66 (1H, dd, J=2.2, 7.7 Hz), 2.89 (1H, dt,J=2.2, 5.5 Hz), 3.49-3.56 (3H, m), 3.58-3.67 (2H, m), 3.75-3.81 (1H, m),4.94 (1H, d, J=9.5 Hz), 5.06 (1H, d, J=10.6 Hz), 5.57 (1H, dd, J=9.9,15.0 Hz), 5.72 (1H, dd, J=9.5, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz), 6.13(1H, d, J=9.9 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 651(M+H)⁺.

Example 10(8E,12E,14E)-7-(N-(3-(N′,N′-Dimethylamino)propyl)carbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 10)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.20 (3H, s), 1.20-1.26 (1H,m), 1.33 (3H, s), 1.33-1.71 (9H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.5,14.3 Hz), 2.25 (6H, s), 2.36 (2H, t, J=7.3 Hz), 2.49-2.61 (3H, m), 2.66(1H, dd, J=2.2, 8.1 Hz), 2.89 (1H, dt, J=2.2, 5.5 Hz), 3.13 (2H, t,J=6.6 Hz), 3.52 (1H, dt, J=4.4, 8.1 Hz), 3.75-3.81 (1H, m), 4.89 (1H, d,J=9.5 Hz), 5.05 (1H, d, J=10.6 Hz), 5.55 (1H, dd, J=9.5, 15.4 Hz), 5.69(1H, dd, J=9.5, 15.4 Hz), 5.86 (1H, d, J=15.4 Hz), 6.13 (1H, d, J=10.6Hz), 6.52 (1H, dd, J=10.6, 15.4 Hz); ESI-MS m/z 639 (M+H)⁺.

Example 11(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-((pyridin-4-yl)methyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 11)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=5.1 Hz), 0.89(3H, d, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz), 1.23 (3H, s), 1.23-1.27 (1H,m), 1.33 (3H, s), 1.33-1.62 (6H, m), 1.65 (1H, dd, J=6.2, 14.3 Hz), 1.77(3H, s), 1.86 (1H, dd, J=6.2, 14.3 Hz), 2.48-2.65 (3H, m), 2.66 (1H, dd,J=2.2, 8.1 Hz), 2.89 (1H, dt, J=2.2, 6.2 Hz), 3.52 (1H, dt, J=4.4, 8.1Hz), 3.74-3.80 (1H, m), 4.35 (2H, s), 4.93 (1H, d, J=9.5 Hz), 5.06 (1H,d, J=10.6 Hz), 5.56 (1H, dd, J=9.5, 15.4 Hz), 5.73 (1H, dd, J=9.5, 15.4Hz), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, d,J=11.0, 15.0 Hz), 7.33 (2H, d, J=5.9 Hz), 8.45 (2H, dd, J=1.5, 4.4 Hz);ESI-MS m/z 645 (M+H)⁺.

Example 12(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12)

First Step(8E,12E,14E)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12-1)

A solution of Compound 46-4(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(628 mg, 0.575 mmol) obtained in the fourth step of Example 46 intetrahydrofuran (7 mL) was cooled to 5° C., and a solution of1-methylpiperazine (118 mg, 1.152 mmol) in tetrahydrofuran (1.5 mL) anda solution of triethylamine (236 mg, 2.305 mmol) in tetrahydrofuran (1.5mL) were added dropwise thereto. The reaction mixture was stirred atroom temperature for 1.5 hours. The reaction mixture was diluted withethyl acetate, and washed with an aqueous solution of sodium bicarbonateand brine. The organic layer was dried over anhydrous magnesium sulfate,filtrated and evaporated. The resulting residue was purified by silicagel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethylacetate-hexane-methanol, 1:1:0 to 4:1:0 to 9:1:0 to 1:0:0 to 39:0:1 to19:0:1) to give the title compound (514 mg, 85%) as a colorless oil.

Second Step(8E,12E,14E)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12-2)

A solution of Compound 12-1(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(514 mg, 0.489 mmol) obtained in the first step in tetrahydrofuran (10mL) was cooled to 5° C., and tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 1.62 mL, 1.62 mmol) was added dropwisethereto. The reaction mixture was stirred at room temperature for twohours. Additional tetrabutylammonium fluoride (1.0 M tetrahydrofuransolution, 0.3 mL, 0.3 mmol) was added dropwise, and the reaction mixturewas stirred at room temperature for one hour. The reaction mixture wasdiluted with ethyl acetate and washed with an aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous magnesiumsulfate, filtrated and evaporated. The resulting residue was purified bysilica gel column chromatography (Fuji Silysia, NH Silica gel, 200 to350 mesh; ethyl acetate-hexane-methanol, 1:1:0 to 4:1:0 to 1:0:0 to49:0:1 to 19:0:1) to give the title compound (364 mg, 99%) as acolorless oil.

ESI-MS m/z 709 (M+H)⁺

Third Step(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 12)

To a solution of Compound 12-2(8E,12E,14E)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(364 mg, 0.489 mmol) obtained in the second step in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (10 mL) was added pyridiniump-toluenesulfonate (184 mg, 0.734 mmol), and the reaction mixture wasstirred at room temperature for 19 hours. After triethylamine (75 mg,0.734 mmol) was added dropwise to the reaction mixture, the mixture wasevaporated. The resulting residue was dissolved in ethyl acetate andwashed with a saturated aqueous solution of sodium bicarbonate. Theorganic layer was dried over anhydrous magnesium sulfate, filtrated andevaporated. The resulting residue was purified by silica gel columnchromatography (Fuji Silysia, NH Silica gel, 200 to 350 mesh; ethylacetate-hexane-methanol, 1:1:0 to 2:1:0 to 4:1:0 to 1:0:0 to 39:0:1 to29:0:1 to 19:0:1). The crude purified fraction was evaporated, and theresidue was purified by thin layer chromatography (Fuji Silysia, NHSilica gel Plate; methanol-dichloromethane, 1:29) to give the titlecompound (286 mg, 92%) as a colorless oil.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.28 (4H, m), 1.32-1.68(10H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.6, 14.4 Hz), 2.30(3H, s), 2.36-2.44 (4H, m), 2.50-2.64 (3H, m), 2.66 (1H, dd, J=2.4, 8.0Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.38-3.70 (5H, m), 3.75-3.81 (1H, m),4.93 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0,15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 637(M+H)⁺.

Example 13(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 13)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.20-1.30 (4H, m), 1.32-1.68(10H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.6, 14.4 Hz),2.50-2.64 (3H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.76 (4H, t, J=5.2 Hz),2.89 (1H, dt, J=2.4, 5.6 Hz), 3.34-3.68 (5H, m), 3.75-3.81 (1H, m), 4.94(1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H,d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 623 (M+H)⁺.

Example 14(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyridin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 14)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.20-1.30 (4H, m), 1.32-1.69(10H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.6, 14.4 Hz),2.50-2.64 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4,6.0 Hz), 3.38-3.46 (4H, m), 3.49-3.84 (6H, m), 4.97 (1H, d, J=1.0 Hz),5.06 (1H, d, J=10.8 Hz), 5.59 (1H, dd, J=10.0, 15.2 Hz), 5.74 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53(1H, dd, J=11.2, 15.2 Hz), 6.86 (2H, d, J=6.8 Hz), 8.13 (2H, d, J=6.8Hz); ESI-MS m/z 700 (M+H)⁺.

Example 15(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 15)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69(12H, m), 1.72-1.90 (6H, m), 2.06-2.22 (2H, m), 2.28 (3H, s), 2.50-2.64(3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.76-2.98 (6H, m), 3.52 (1H, dt,J=4.4, 8.4 Hz), 3.75-3.82 (1H, m), 3.85-4.14 (1H, m), 4.95 (1H, d,J=10.0 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz),5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 665 (M+H)⁺.

Example 16(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 16)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 0.94 (3H, t, J=7.6 Hz),1.19-1.69 (18H, m), 1.77 (3H, d, J=1.2 Hz), 1.86 (1H, dd, J=5.6, 14.0Hz), 2.34-2.64 (9H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.4, 6.4 Hz), 3.38-3.72 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J=9.6Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.71 (1H,dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz),6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 17(8E,12E,14E)-7-((4-Benzylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 17)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.85-0.92 (6H, m), 0.94 (3H,t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.78 (3H, s),1.79-1.90 (3H, m), 2.50-2.72 (8H, m), 2.89 (1H, dt, J=2.4, 6.0 Hz),3.42-3.68 (7H, m), 3.75-3.82 (1H, m), 4.91-4.97 (1H, m), 5.06 (1H, d,J=10.8 Hz), 5.53-5.62 (1H, m), 5.67-5.77 (1H, m), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz), 7.21-7.35(5H, m); ESI-MS m/z 727 (M+H)⁺.

Example 18(8E,12E,14E)-7-((4-(3-Chloropropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 18)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69(10H, m), 1.77 (3H, d, J=0.8 Hz), 1.80-1.96 (5H, m), 2.49-2.74 (10H, m),2.89 (1H, dt, J=2.4, 6.4 Hz), 3.41-3.69 (7H, m), 3.75-3.81 (1H, m),4.92-4.97 (1H, m), 5.07 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=9.6, 15.2Hz), 5.73 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H,d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 713 (M)⁺.

Example 19(8E,12E,14E)-7-((4-(N,N-Dimethylamino)piperidin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 19)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.68 (16H, m), 1.77 (3H,d, J=0.8 Hz), 1.83-1.93 (3H, m), 2.28 (6H, s), 2.38 (1H, tt, J=3.6, 11.6Hz), 2.49-2.62 (3H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.71-2.88 (2H, m),2.89 (1H, dt, J=2.4, 6.0 Hz), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.75-3.82(1H, m), 4.08-4.45 (2H, m), 4.92 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 665 (M+H)⁺.

Example 20(8E,12E,14E)-7-((1,4-Diazabicyclo[4,3,0]nonane-4-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 20)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69(10H, m), 1.73-2.02 (6H, m), 2.09-2.22 (2H, m), 2.49-2.71 (6H, m),2.87-3.12 (6H, m), 3.52 (1H, dt, J=4.4, 8.0 Hz), 3.75-3.82 (1H, m),4.01-4.51 (2H, m), 4.88-4.99 (1H, m), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H,dd, J=9.6, 14.8 Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z663 (M+H)⁺.

Example 21(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 21)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.11 (3H, t, J=7.6 Hz), 1.21(3H, s), 1.22-1.64 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J=6.2, 14.2 Hz),1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.39-2.49 (6H, m),2.50-2.53 (2H, m), 2.53-2.62 (1H, m), 2.66 (1H, dd, J=2.4, 7.6 Hz), 2.89(1H, dt, J=2.0, 6.0 Hz), 3.34-3.72 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H,d, J=9.6 Hz), 5.05 (1H, d, J=10.4 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz),5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (H, d,J=10.8 Hz), 6.52 (H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 651 (M+H)⁺.

Example 22(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 22)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.20-1.69 (16H,m), 1.34 (3H, s), 1.77 (3H, s), 1.83-1.93 (3H, m), 2.45-2.65 (8H, m),2.66 (1H, dd, J=2.4, 7.6 Hz), 2.70-2.85 (2H, m), 2.89 (1H, dt, J=2.4,6.0 Hz), 3.51 (1H, td, J=4.4, 8.0 Hz), 3.74-3.82 (1H, m), 4.12-4.25 (1H,m), 4.30-4.45 (1H, m), 4.92 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz),5.56 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.6 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 705 (M+H)⁺.

Example 23(8E,12E,14E)-7-((Homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 23)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.4 Hz), 1.23 (3H, s), 1.24-1.69 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.78-1.90 (3H, m), 2.48-2.62 (3H, m),2.66 (1H, dd, J=2.4, 8.0 Hz), 2.72-2.93 (5H, m), 3.43-3.67 (5H, m),3.74-3.82 (1H, m), 4.94 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57(1H, dd, J=10.4, 15.2 Hz), 5.72 (1H, dd, J=9.8, 15.4 Hz), 5.86 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.0, 15.4 Hz);EI-MS m/z 637 (M+H)⁺.

Example 24(8E,12E,14E)-7-((4-Benzylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 24)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.20 (3H, s), 1.22-1.65 (7H,m), 1.34 (3H, s), 1.65 (1H, dd, J=6.2, 14.2 Hz), 1.77 (3H, s), 1.87 (1H,dd, J=5.4, 14.2 Hz), 2.39-2.49 (4H, m), 2.50-2.64 (3H, m), 2.67 (1H, dd,J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 5.6 Hz), 3.36-3.72 (7H, m),3.74-3.83 (1H, m), 4.92 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.56(1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz),7.22-7.37 (5H, m); ESI-MS m/z 713 (M+H)⁺.

Example 25(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 25)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.86-0.97 (12H, m), 1.21 (3H,s), 1.21-1.68 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.87 (1H, dd, J=5.2,14.0 Hz), 2.30-2.36 (2H, m), 2.38-2.47 (4H, m), 2.49-2.63 (3H, m), 2.66(1H, dd, J=2.4, 7.6 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.35-3.72 (5H,m), 3.74-3.83 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz),5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=1.0, 15.2 Hz), 5.87 (1H,d, J=15.2 Hz), 6.13 (1H, d, J=10.0 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 665 (M+H)⁺.

Example 26(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 26)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.10-1.69 (15H, m), 1.21 (3H,s), 1.34 (3H, s), 1.78 (3H, s), 1.78-1.93 (4H, m), 2.26-2.35 (1H, m),2.47-2.64 (7H, m), 2.67 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.0,6.0 Hz), 3.36-3.70 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz),5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53(1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 27(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 27)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.12-0.17 (2H, m), 0.52-0.58(2H, m), 0.89 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 0.90-0.97 (4H,m), 1.21 (3H, s), 1.21-1.69 (8H, m), 1.34 (3H, s), 1.78 (3H, s), 1.86(1H, dd, J=5.2, 14.0 Hz), 2.29 (2H, d, J=6.8 Hz), 2.47-2.64 (7H, m),2.67 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.40-3.72(5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 677 (M+H)⁺.

Example 28(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 28)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.68(12H, m), 1.77 (3H, d, J=1.2 Hz), 1.83-1.95 (3H, m), 2.34-2.43 (1H, m),2.50-2.64 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.73-2.89 (2H, m), 2.89(1H, dt, J=2.4, 6.0 Hz), 3.52 (1H, td, J=4.4, 8.0 Hz), 3.66-3.72 (4H,m), 3.75-3.81 (1H, m), 4.07-4.44 (2H, m), 4.92 (1H, d, J=9.6 Hz), 5.06(H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72 (1H, dd, J=9.6,15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H,dd, J=10.8, 15.2 Hz); ESI-MS m/z 707 (M+H)⁺.

Example 29(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3,3,3-trifluoropropyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 29)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.69(10H, m), 1.77 (3H, d, J=1.2 Hz), 1.86 (1H, dd, J=5.6, 14.0 Hz),2.35-2.66 (11H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0,6.0 Hz), 3.38-3.71 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J=10.0 Hz),5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53(1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 719 (M+H)⁺, 741 (M+Na)⁺.

Example 30(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(4,4,4-trifluorobutyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 30)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69(10H, m), 1.70-1.81 (5H, m), 1.86 (1H, dd, J=5.6, 14.0 Hz), 2.14-2.28(2H, m), 2.38-2.49 (6H, m), 2.50-2.64 (3H, m), 2.67 (1H, dd, J=2.4, 8.0Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.39-3.72 (5H, m), 3.75-3.82 (1H, m),4.93 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0,15.2 Hz), 5.72 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 733(M+H)⁺, 755 (M+Na)⁺.

Example 31(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 31)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.87-0.92 (9H, m), 0.94 (3H,t, J=7.6 Hz), 1.20-1.30 (4H, m), 1.32-1.69 (12H, m), 1.77 (3H, d, J=0.8Hz), 1.82-1.91 (3H, m), 2.41-2.49 (2H, m), 2.50-2.77 (8H, m), 2.89 (1H,dt, J=2.4, 6.0 Hz), 3.42-3.67 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d,J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.73(1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 32(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-(2-methoxyethyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 32)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.69(10H, m), 1.77 (3H, d, J=1.2 Hz), 1.86 (1H, dd, J=5.6, 14.0 Hz),2.44-2.64 (9H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4,6.0 Hz), 3.33 (3H, s), 3.39-3.71 (7H, m), 3.75-3.82 (1H, m), 4.93 (1H,d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz),5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 681 (M+H)⁺.

Example 33(8E,12E,14E)-7-((4-Cyclobutylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 33)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69(10H, m), 1.70-1.81 (5H, m), 1.83-1.95 (3H, m), 2.02-2.11 (2H, m),2.27-2.37 (4H, m), 2.49-2.64 (3H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz),2.72-2.81 (1H, m), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.37-3.71 (5H, m),3.75-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57(1H, dd, J=9.6, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 677 (M+H)⁺.

Example 34(8E,12E,14E)-7-((4-(1-Ethylpropyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 34)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.87-0.97 (15H, m), 1.19-1.69(18H, m), 1.77 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0 Hz),2.15-2.23 (1H, m), 2.45-2.64 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89(1H, dt, J=2.4, 6.0 Hz), 3.34-3.65 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H,d, J=10.0 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz),5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (H, d, J=15.2 Hz), 6.13 (1H, d,J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 693 (M+H)⁺.

Example 35(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(tetrahydropyran-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 35)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.21-1.69 (10H,m), 1.34 (3H, s), 1.77 (3H, s), 1.77-1.90 (3H, m), 2.42-2.62 (8H, m),2.66 (1H, dd, J=2.0, 7.6 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.34-3.71(7H, m), 3.74-3.82 (1H, m), 3.94-4.02 (2H, m), 4.93 (1H, d, J=9.6 Hz),5.05 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.4 Hz), 6.53(1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 707 (M+H)⁺.

Example 36(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 36)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.08-0.14 (2H, m), 0.48-0.54(2H, m), 0.83 (3H, d, J=6.8 Hz), 0.88 (3H, d, J=7.2 Hz), 0.89-0.94 (4H,m), 1.20-1.67 (8H, m), 1.21 (3H, s), 1.31 (3H, s), 1.75 (3H, s),1.80-1.90 (3H, m), 2.37 (2H, d, J=6.4), 2.47-2.61 (3H, m), 2.62-2.82(5H, m), 2.87 (1H, dt, J=2.4, 6.0 Hz), 3.43-3.69 (5H, m), 3.73-3.80 (1H,m), 4.92 (1H, d, J=9.6 Hz), 5.04 (1H, d, J=10.8 Hz), 5.55 (1H, dd,J=10.0, 15.2 Hz), 5.70 (H, dd, J=9.6, 15.2 Hz), 5.84 (1H, d, J=15.2 Hz),6.11 (1H, d, J=11.2 Hz), 6.50 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 691(M+H)⁺.

Example 37(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 37)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.20-1.69 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.4 Hz), 2.50-2.69(8H, m), 2.86-2.92 (1H, m), 3.38-3.72 (2H, m), 3.04-3.14 (5H, m),3.74-3.82 (1H, m), 4.93 (1H, d, J=10.0 Hz), 5.05 (1H, d, J=10.8 Hz),5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.2 Hz), 5.87(1H, d, J=15.6 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 727 (M+Na)⁺.

Example 38(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 38)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.21-1.76 (14H,m), 1.34 (3H, s), 1.77 (3H, s), 1.83-1.95 (3H, m), 2.46-2.62 (8H, m),2.66 (1H, dd, J=2.4, 7.6 Hz), 2.88 (1H, dt, J=2.4, 6.4 Hz), 3.34-3.72(5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J=10.0 Hz), 5.05 (1H, d, J=10.4Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.2 Hz),5.87 (1H, d, J=15.6 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2,15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 39(8E,12E,14E)-7-((4-Isobutylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 39)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.87-0.97 (15H, m), 1.21 (3H,s), 1.21-1.69 (8H, m), 1.34 (3H, s), 1.77 (3H, s), 1.78-1.90 (2H, m),2.11 (2H, d, J=7.2 Hz), 2.32-2.41 (4H, m), 2.50-2.63 (3H, m), 2.67 (1H,dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.38-3.70 (5H, m),3.74-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.05 (1H, d, J=10.4 Hz), 5.57(1H, dd, J=9.6, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d,J=15.6 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 679 (M+H)⁺.

Example 40(8E,12E,14E)-7-(((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 40)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.84 (3H, d, J=7.0 Hz), 0.85(3H, d, J=7.0 Hz), 0.89 (3H, t, J=7.3 Hz), 1.14-1.27 (4H, m), 1.27-1.65(7H, m), 1.30 (3H, s), 1.65-1.92 (6H, m), 2.44-2.66 (5H, m), 2.79-2.88(2H, m), 3.16 (0.6H, dd, J=1.8, 10.3 Hz), 3.25-3.31 (0.4H, m), 3.45-3.78(6H, m), 4.29 (0.4H, brs), 4.52 (0.6H, brs), 4.89 (1H, d, J=9.9 Hz),5.02 (1H, d, J=10.6 Hz), 5.54 (1H, dd, J=9.9, 15.0 Hz), 5.68 (0.6H, dd,J=9.9, 15.0 Hz), 5.73 (0.4H, dd, J=9.9, 15.0 Hz), 5.82 (1H, d, J=15.4Hz), 6.09 (1H, d, J=11.0 Hz), 6.48 (1H, d, J=11.0, 15.4 Hz), 7.16-7.32(5H, m); ESI-MS m/z 725 (M+H)⁺.

Example 41(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-ethylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 41)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.08-1.14 (3H, m), 1.20-1.29(1H, m), 1.22 (3H, s), 1.31-1.68 (7H, m), 1.33 (3H, s), 1.77 (3H, d,J=0.7 Hz), 1.86 (1H, dd, J=5.5, 14.3 Hz), 2.28 (6H, s), 2.43-2.62 (5H,m), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.89 (1H, dt, J=2.2, 5.5 Hz),3.23-3.52 (4H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.74-3.82 (1H, m), 4.92(1H, d, J=9.9 Hz), 5.06 (1H, d, J=10.6 Hz), 5.56 (1H, dd, J=9.9, 15.0Hz), 5.73 (1H, dd, J=9.9, 15.0 Hz), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H,dd, J=1.1, 11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 653(M+H)⁺.

Example 42(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-ethylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 42)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.06 (6H, t, J=7.0 Hz),1.06-1.15 (3H, m), 1.20-1.29 (1H, m), 1.22 (3H, s), 1.31-1.68 (7H, m),1.33 (3H, s), 1.77 (3H, d, J=1.1 Hz), 1.86 (1H, dd, J=5.5, 14.3 Hz),2.48-2.66 (5H, m), 2.59 (4H, q, J=7.0 Hz), 2.66 (1H, dd, J=2.2, 8.1 Hz),2.89 (1H, dt, J=2.2, 5.5 Hz), 3.21-3.60 (4H, m), 3.52 (1H, dt, J=4.4,8.4 Hz), 3.74-3.81 (1H, m), 4.93 (1H, d, J=9.9 Hz), 5.06 (1H, d, J=10.6Hz), 5.57 (1H, dd, J=9.9, 15.0 Hz), 5.73 (1H, dd, J=9.9, 15.0 Hz), 5.86(1H, d, J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4Hz); ESI-MS m/z 681 (M+H)⁺.

Example 43(8E,12E,14E)-7-Acetoxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 43)

(8E,12E,14E)-7-Acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(34 mg, 44 mol) obtained in Example 3 and1,8-bis(N,N-dimethylamino)naphthalene (57 mg, 266 μmol) were dissolvedin toluene (2 mL). Methyl trifluoromethanesulfonate (22 mg, 133 mol) wasadded to this solution, and the reaction mixture was stirred at 65° C.for 11 hours. After removing the precipitate by filtration, the reactionmixture was diluted with ethyl acetate, and an aqueous solution ofammonium chloride was added, followed by vigorous stirring for 5minutes. The organic layer was washed with a saturated aqueous solutionof sodium bicarbonate and brine, dried over anhydrous magnesium sulfate,and concentrated. The resulting residue was purified by silica gelcolumn chromatography (Kanto silica gel 60N spherical, neutral, 40 to100 μm; hexane:ethyl acetate=1:1) to give(8E,12E,14E)-7-acetoxy-3,16,21-tris(1-ethoxyethoxy)-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(14 mg) as a colorless oil.

The obtained compound was subjected to deprotection of ethoxyethyl groupby a similar method as described for Example 3, to give the titlecompound (5.7 mg, 22.9%, two steps) as a colorless oil.

¹H-NMR Spectrum (CD₃ OD, 500 MHz) δ(ppm): 0.88 (3H, d, J=6.5 Hz), 0.91(3H, d, J=7.5 Hz), 0.94 (3H, t, J=7.5 Hz), 1.21 (3H, s), 1.22-1.32 (1H,m), 1.34 (3H, s), 1.40-1.70 (7H, m), 1.78 (3H, s), 1.86 (1H, dd, J=5.5,14.0 Hz), 2.06 (3H, s), 2.46-2.63 (3H, m), 2.67 (1H, d, J=8.5 Hz), 2.99(1H, brs), 3.33 (3H, s), 3.50-3.56 (1H, m), 3.78-3.86 (1H, m), 5.06 (1H,d, J=10.5 Hz), 5.12 (1H, d, J=10.0 Hz), 5.56 (1H, dd, J=10.0, 15.5 Hz),5.72 (1H, dd, J=10.5, 15.5 Hz), 5.87 (1H, d, J=15.5 Hz), 6.14 (1H, d,J=10.5 Hz), 6.53 (1H, dd, J=10.5, 15.5 Hz); ESI-MS m/z 589 (M+Na)⁺.

Example 44(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44)

First Step

(8E,12E,14E)-6-(1-Ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44-1)

To a solution of Compound 46-4(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.27 g, 1.16 mmol) obtained in the fourth step of Example 46 intetrahydrofuran (25 mL) were added triethylamine (470 mg, 4.64 mmol) andisopropylpiperazine (298 mg, 2.32 mmol) at room temperature, and thereaction mixture was stirred at the same temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate and then washed with asaturated aqueous solution of sodium bicarbonate and brine. The organiclayer was dried over anhydrous magnesium sulfate, filtrated andconcentrated. The resulting residue was purified by silica gel columnchromatography (Kanto silica gel 60N, 40 to 100 μm; hexane:ethylacetate=1:1 to ethyl acetate to ethyl acetate:methanol=97:3) to give thetitle compound (0.12 g, 89%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.58-0.70 (27H, m), 0.80-1.72(53H, m), 1.76 (3H, s), 1.88-1.98 (1H, m), 2.33-2.64 (8H, m), 2.64-2.76(1H, m), 2.80-2.90 (1H, m), 3.38-3.66 (6H, m), 3.68-3.78 (1H, m),3.85-3.98 (1H, m), 4.88-4.99 (2H, m), 5.05 (0.4H, q, J=5.2 Hz), 5.13(0.6H, q, J=5.2 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72-5.80 (1H, m),5.82 (1H, d, J=14.8 Hz), 6.13 (1H, d, J=10.8 Hz), 6.50 (1H, dd, J=10.8,15.2 Hz).

Second Step

(8E,12E,14E)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44-2)

To a solution of Compound 44-1(8E,12E,14E)-6-(1-ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.12 g, 1.03 mmol) obtained in the first step in tetrahydrofuran (20mL) was added tetrabutylammonium fluoride (4.1 mL, 1.0 M tetrahydrofuransolution) at room temperature, and the reaction mixture was stirred atthe same temperature for 4 hours. The reaction mixture was diluted withethyl acetate and then washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and evaporated. The resulting residue waspurified by silica gel column chromatography (Fuji Silysia, NH Silicagel, 200-350 mesh; ethyl acetate to ethyl acetate:methanol=95:5) to givethe title compound (0.76 g, 99%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.06 (6H, d, J=6.4 Hz),1.12-1.70 (20H, m), 1.78 (3H, s), 1.86 (1H, dd, J=2.4, 7.6 Hz),2.42-2.62 (7H, m), 2.64-2.76 (2H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.38-3.66 (7H, m), 3.75-3.84 (1H, m), 4.98 (1H, d, J=9.6 Hz), 5.02-5.16(2H, m), 5.56 (1H, dd, J=10.0, 15.6 Hz), 5.72-5.80 (1H, m), 5.87 (1H, d,J=15.6 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 737 (M+H)⁺.

Third Step

(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 44)

To a solution of Compound 44-2(8E,12E,14E)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(0.76 g, 1.03 mmol) obtained in the second step in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (20 mL) was added pyridiniump-toluenesulfonate (0.39 g, 1.55 mmol) at room temperature, and thereaction mixture was stirred at the same temperature for 16 hours.Triethylamine (0.25 g, 3.10 mmol) was added to the reaction mixture atroom temperature, and the organic solvent was evaporated. The resultingresidue was diluted with ethyl acetate and washed with a saturatedaqueous solution of sodium bicarbonate and brine. The organic layer wasdried over anhydrous sodium sulfate, filtrated and evaporated. Theresulting residue was purified by silica gel column chromatography (FujiSilysia, NH Silica gel, 200-350 mesh; ethyl acetate to ethylacetate:methanol=95:5) to give the title compound (0.76 g, 85%) as acolorless oil.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.6 Hz), 0.90(3H, d, J=6.9 Hz), 0.94 (3H, t, J=7.4 Hz), 1.07 (6H, d, J=6.4 Hz),1.14-1.67 (14H, m), 1.77 (3H, brs), 1.86 (1H, dd, J=5.4, 14.2 Hz),2.46-2.63 (7H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.64-2.79 (1H, m), 2.89(1H, dt, J=2.4, 6.0 Hz), 3.36-3.67 (5H, m), 3.72-3.81 (1H, m), 4.93 (1H,d, J=9.7 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.7, 15.1 Hz),5.71 (1H, dd, J=9.7, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 665 (M+H)⁺.

Example 45(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 45)

First Step

(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 45-1)

To a solution of Compound 46-4(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.368 g, 1.254 mmol) obtained in the fourth step of Example 46 intetrahydrofuran (20 mL) were sequentially added dropwise1-cycloheptylpiperazine (462 mg, 2.51 mmol) and triethylamine (513 mg,5.02 mmol). Then, tetrahydrofuran (8 mL) was added thereto, and thereaction mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate and washed with anaqueous solution of sodium bicarbonate and brine. The organic layer wasdried over anhydrous magnesium sulfate, filtrated and concentrated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1:9 to 1:4 to1:3) to give the title compound (1.455 g, 99%) as a colorless oil.

Second Step

(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 45-2)

A solution of Compound 45-1(8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.454 g, 1.254 mmol) obtained in the first step in tetrahydrofuran (30mL) was cooled to 5° C., tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 4.5 mL, 4.5 mmol) was added dropwise thereto,and the reaction mixture was stirred at room temperature for 1.5 hours.Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.52 mL,0.52 mmol) was further added dropwise, and the reaction mixture wasstirred at room temperature for two hours. The reaction mixture wasdiluted with ethyl acetate and washed with an aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Fuji Silysia, NH Silicagel, 200-350 mesh; ethyl acetate-hexane, 1:1 to 4:1 to 9:1 to 1:0) togive the title compound (965 mg, 97%) as a colorless oil.

ESI-MS m/z 791 (M+H)⁺

Third Step

(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 45)

To a solution of Compound 45-2(8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-olide(964 mg, 1.218 mmol) obtained in the second step in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (22 mL) was added pyridiniump-toluenesulfonate (459 mg, 1.827 mmol), and the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with ethyl acetate and washed with an aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Fuji Silysia, NH Silicagel, 200 to 350 mesh; ethyl acetate-hexane-methanol, 2:1:0 to 4:1:0 to99:0:1 to 98:0:1 to 97:0:1), and the crude fraction was concentrated.The resulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40-50 μm; methanol-dichloromethane, 1:29 to 1:19to 1:17 to 1:14 to 1:9) to give the title compound (866 mg, 99%) as acolorless oil.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.10-1.77 (24H, m), 1.77 (3H,brs), 1.79-1.90 (3H, m), 2.42-2.74 (9H, m), 2.85-2.92 (1H, m), 3.36-3.70(5H, m), 3.72-3.84 (1H, m), 4.92 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 719 (M+H)⁺.

Example 46(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46)

First Step

(8E,12E,14E)-7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46-1)

To a solution of(8E,12E,14E)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(100 mg, 0.18 mmol) in dichloromethane (6 mL) were addedN,N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane(272 mg, 1.8 mmol) at room temperature, and the reaction mixture wasstirred at the same temperature for 18 hours. The reaction mixture wasdiluted with ethyl acetate and washed with saturated aqueous solution ofammonium chloride and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N,40-100 μm; ethyl acetate:hexane=20:80) to give the title compound (159mg, 98%) as a colorless oil. ESI-MS m/z 918 (M+Na)⁺.

Second Step

(8E,12E,14E)-7-Acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46-2)

To a solution of Compound 46-1(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.6 g, 1.8 mmol) obtained in the first step in dichloromethane (35 mL)were added ethyl vinyl ether (2.6 g, 36 mmol) and pyridiniump-toluenesulfonate (22 mg, 89 μmol) at room temperature, and theresulting mixture was stirred at the same temperature for 19 hours. Thereaction mixture was washed with a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N,40-100 μm; ethyl acetate:hexane=10:90) to give the title compound (1.6g, 93%) as a colorless oil.

ESI-MS m/z 990 (M+Na)⁺.

Third Step

(8E,12E,14E)-6-(1-Ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46-3)

To Compound 46-2(8E,12E,14E)-7-acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.6 g, 1.7 mmol) obtained in the second step was addedguanidine/guanidine nitrate (41 mL, 0.2M dichloromethane:methanol=10:90solution) at room temperature, followed by stirring at the sametemperature for three hours. The reaction mixture was diluted with ethylacetate and washed with a saturated aqueous solution of ammoniumchloride and brine. The organic layer was dried over anhydrous magnesiumsulfate, filtrated and concentrated. The resulting residue was purifiedby silica gel column chromatography (Kanto silica gel 60N, 40-100 μm;ethyl acetate:hexane=20:80) to give the title compound (1.3 g, 84%) as acolorless oil. ESI-MS m/z 948 (M+Na)⁺.

Fourth Step

(8E,12E,14E)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46-4)

To a solution of Compound 46-3(8E,12E,14E)-6-(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(1.3 g, 1.4 mmol) obtained in the third step in dichloromethane (30 mL)were added triethylamine (826 mg, 8.2 mmol), N,N-dimethylaminopyridine(831 mg, 6.8 mmol) and 4-nitrophenyl chloroformate (823 mg, 4.1 mmol) atroom temperature, and the resulting mixture was stirred at the sametemperature for 1.5 hours. The reaction mixture was diluted withdichloromethane and washed with a saturated aqueous solution of ammoniumchloride, a saturated aqueous solution of sodium bicarbonate and brine.The organic layer was dried over anhydrous magnesium sulfate, filtratedand concentrated. The resulting residue was purified by silica gelcolumn chromatography (Kanto silica gel 60N, 40-100 μm; ethylacetate:hexane=10:90) to give the title compound (1.4 g, 97%) as acolorless oil.

ESI-MS m/z 1114 (M+Na)⁺.

Fifth Step(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46-5)

To a solution of Compound 46-4(8E,12E,14E)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(37 mg, 34 μmol) obtained in the fourth step in tetrahydrofuran (2 mL)were added triethylamine (14 mg, 0.14 mmol) and allylpiperazine (8.5 mg,68 μmol) at room temperature, and the resulting mixture was stirred atthe same temperature for 1.5 hours. The reaction mixture was dilutedwith ethyl acetate and washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N,40-100 μm; ethyl acetate:hexane=30:70) to give the title compound (28mg, 77%) as a colorless oil.

ESI-MS m/z 1078 (M+H)⁺.

Sixth Step(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 46)

To a solution of Compound 46-5(8E,12E,14E)-7-((4-allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(26 mg, 24 μmol) obtained in the fifth step in tetrahydrofuran (2.5 mL)was added tetrabutylammonium fluoride (79 μL, 1.0 M tetrahydrofuransolution) at room temperature, and this mixture was stirred at the sametemperature for three hours. The reaction mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by thin layer chromatography (Fuji Silysia, NH Silica gelPlate; methanol:dichloromethane=5:95) to give the title compound (13 mg,72%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.85-0.90 (6H, m), 0.94 (3H, t,J=7.6 Hz), 1.12-1.68 (20H, m), 1.78 (3H, s), 1.86 (1H, dd, J=2.4, 7.6Hz), 2.38-2.62 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.03 (2H, d, J=6.4 Hz), 3.44-3.62 (7H, m), 3.76-3.84(1H, m), 4.94-5.14 (3H, m), 5.16-5.26 (2H, m), 5.56 (1H, dd, J=10.0,15.6 Hz), 5.70-5.82 (3H, m), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 735 (M+H)⁺.

Example 47(8E,12E,14E)-7-((4-Allylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 47)

To Compound 46(8E,12E,14E)-7-((4-allylpiperazin-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(8.7 mg, 12 μmol) obtained in Example 46 was added a solution ofpyridinium p-toluenesulfonate (3.3 mg, 13 μmol) in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (1 mL) at room temperature, andthe reaction mixture was stirred at the same temperature for 17 hours.The reaction mixture was concentrated. The resulting residue waspurified by thin layer chromatography (Fuji Silysia, NH Silica gelPlate; methanol:dichloromethane=5:95) to give the title compound (5.5mg, 70%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.34 (3H, s),1.22-1.68 (8H, m), 1.78 (3H, s), 1.86 (1H, dd, J=2.4, 7.6 Hz), 2.38-2.46(4H, m), 2.48-2.60 (3H, m), 2.67 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt,J=2.0, 5.6 Hz), 3.04 (2H, d, J=6.8 Hz), 3.42-3.64 (5H, m), 3.74-3.82(1H, m), 4.92 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.16-5.26 (2H,m), 5.57 (1H, dd, J=10.0, 15.6 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz),5.82-5.92 (2H, m), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 663 (M+H)⁺.

Example 48(8E,12E,14E)-7-((4-(3,7-Dimethyl-2,6-octadien-1-yl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 48)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.34 (3H, s),1.24-1.68 (8H, m), 1.60 (3H, s), 1.66 (6H, s), 1.77 (3H, s), 1.86 (1H,dd, J=5.6, 14.0 Hz), 2.04-2.16 (4H, m), 2.40-2.46 (4H, m), 2.48-2.62(3H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 5.2 Hz),3.02 (2H, d, J=6.8 Hz), 3.42-3.64 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H,d, J=10.0 Hz), 5.02-5.12 (2H, m), 5.24 (1H, t, J=7.2 Hz), 5.57 (1H, dd,J=10.0, 15.2 Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (H, d, J=15.2 Hz),6.14 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 760(M+H)⁺.

Example 49(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-pentylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 49)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=7.2 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.22-1.68 (20H,m), 1.77 (3H, s), 1.86 (1H, dd, J=5.6, 13.7 Hz), 2.32-2.60 (9H, m), 2.67(1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=1.6, 5.6 Hz), 3.40-3.70 (5H,m), 3.74-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz),5.57 (1H, dd, J=10.8, 15.2 Hz), 5.72 (1H, dd, J=10.8, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=9.2 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 693 (M+H)⁺.

Example 50(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 50)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.06-1.12 (6H, m), 1.18-1.68(16H, m), 1.78 (3H, s), 1.86 (1H, dd, J=5.7, 13.7 Hz), 2.47-2.62 (7H,m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.4 Hz), 3.05(1H, t, J=10.0 Hz), 3.19 (1H, dd, J=2.4, 10.8 Hz), 3.48-3.68 (2H, m),3.78 (1H, brs), 4.92 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.58(1H, dd, J=9.6, 15.2 Hz), 5.68-5.78 (1H, m), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 677(M+H)⁺.

Example 51(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-methyl-2-buten-1-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 51)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.34 (3H, s),1.24-1.64 (8H, m), 1.67 (3H, s), 1.75 (3H, s), 1.77 (3H, s), 1.86 (1H,dd, J=5.6, 14.0 Hz), 2.38-2.48 (4H, m), 2.50-2.53 (2H, m), 2.54-2.62(1H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.00 (2H, d, J=6.8 Hz), 3.42-3.66 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H,d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.25 (1H, t, J=6.8 Hz), 5.57 (1H,dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.4 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z691 (M+H)⁺.

Example 52(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((morpholin-4-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 52)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.93 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.34 (3H, s),1.24-1.70 (8H, m), 1.78 (3H, s), 1.86 (1H, dd, J=5.6, 14.0 Hz),2.50-2.62 (3H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.86-2.92 (1H, m),3.42-3.56 (5H, m), 3.58-3.68 (4H, m), 3.76-3.82 (1H, m), 4.95 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.58 (1H, dd, J=10.0, 15.2 Hz), 5.72(1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 646 (M+Na)⁺.

Example 53(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 53)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.04 (6H, d, J=6.4 Hz), 1.23(3H, s), 1.23-1.69 (9H, m), 1.34 (3H, s), 1.77 (3H, s), 1.77-1.90 (2H,m), 2.47-2.76 (8H, m), 2.84-2.98 (2H, m), 3.42-3.68 (5H, m), 3.74-3.82(1H, m), 4.94 (1H, d, J=9.6 Hz), 5.05 (1H, d, J=10.8 Hz), 5.57 (1H, dd,J=9.6, 15.6 Hz), 5.73 (1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.6 Hz),6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z 679(M+H)⁺.

Example 54(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 54)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.87-0.97 (15H, m), 1.23 (3H,s), 1.23-1.69 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.69-1.90 (2H, m),2.23 (2H, d, J=6.8 Hz), 2.50-2.70 (8H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.43-3.66 (5H, m), 3.74-3.82 (1H, m), 4.94 (1H, d, J=10.0 Hz), 5.06 (1H,d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.6 Hz), 5.73 (1H, dd, J=9.6, 15.6Hz), 5.87 (1H, d, J=15.6 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd,J=11.2, 15.6 Hz); ESI-MS m/z 693 (M+H)⁺.

Example 55(8E,12E,14E)-7-((4-(Cyclopentylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 55)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.15-2.20 (20H, m), 1.23 (3H,s), 1.34 (3H, s), 1.77 (3H, s), 2.42 (2H, d, J=7.2 Hz), 2.46-2.74 (8H,m), 2.86-2.92 (1H, m), 3.40-3.68 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H,d, J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz),5.73 (1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.6 Hz), 6.13 (1H, d,J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.6 Hz); ESI-MS m/z 719 (M+H)⁺.

Example 56(8E,12E,14E)-7-(N-((3S)-1-Ethylpyrrolidin-3-yl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 56)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.12 (3H, t, J=7.6 Hz), 1.23(3H, s), 1.23-1.70 (9H, m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd,J=5.2, 14.0 Hz), 2.08-2.22 (1H, m), 2.38-2.90 (11H, m), 2.90 (3H, s),3.28-3.33 (4H, covered with CD₃OD), 3.49-3.56 (1H, m), 3.75-3.82 (1H,m), 4.87-4.93 (1H, covered with H₂O), 5.06 (1H, d, J=10.4 Hz), 5.58 (1H,dd, J=9.6, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.6Hz), 6.13 (1H, d, J1.2 Hz), 6.52 (1H, dd, J=1.2, 15.6 Hz); ESI-MS m/z665 (M+H)⁺.

Example 57(8E,12E,14E)-7-((4-(Cyclobutylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 57)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (6H, d, J=6.8 Hz), 0.94(3H, t, J=7.2 Hz), 1.23 (3H, s), 1.23-1.96 (16H, m), 1.34 (3H, s), 1.77(3H, s), 2.02-2.12 (2H, m), 2.50-2.64 (8H, m), 2.64-2.70 (2H, m),2.86-2.92 (1H, m), 3.40-3.68 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d,J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.72(1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 58(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 58)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.20-2.03 (17H, m), 1.23 (3H,s), 1.34 (3H, s), 1.77 (3H, s), 2.38-2.70 (11H, m), 2.85-2.92 (1H, m),3.33-3.44 (1H, m), 3.49-3.56 (1H, m), 3.75-3.82 (1H, m), 3.93-4.08 (2H,m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57 (1H, dd,J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 691(M+H)⁺.

Example 59(8E,12E,14E)-7-(((3S)-3,4-Dimethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 59)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.08 (3H, d, J=6.4 Hz), 1.21(3H, s), 1.221-1.69 (8H, m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd,J=5, 2, 14.0 Hz), 2.02-2.23 (2H, m), 2.30 (3H, s), 2.46-2.84 (6H, m),2.89 (1H, dt, J=2.0, 5.6 Hz), 2.94-3.12 (1H, m), 3.48-3.55 (1H, m),3.75-3.82 (1H, m), 3.82-4.20 (2H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2Hz), 5.87 (11H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 651 (M+H)⁺.

Example 60(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(prop-2-yn-1-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 60)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.22-1.69 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=5, 6, 14.0 Hz),2.50-2.64 (7H, m), 2.64-2.70 (2H, m), 2.89 (1H, dt, J=2.0, 5.6 Hz), 3.30(2H, d, J=2.4 Hz), 3.40-3.74 (5H, m), 3.75-3.82 (1H, m), 4.93 (11H, d,J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.58 (1H, dd, J=9.6, 15.2 Hz), 5.71(1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 661 (M+H)⁺.

Example 61(8E,12E,14E)-7-((4-(But-2-yn-1-yl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 61)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.22-1.69 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.80 (3H, t, J=2.4 Hz), 1.86 (1H, dd,J=14.0, 5, 6 Hz), 2.45-2.64 (7H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89(1H, dt, J=2.0, 6.0 Hz), 3.25 (2H, q, J=2.4 Hz) 3.40-3.72 (5H, m),3.74-3.82 (1H, m), 4.93 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57(1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=10.6, 15.2 Hz), 5.87 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=111.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 675 (M+H)⁺.

Example 62(8E,12E,14E)-7-((4-Cyclobutylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 62)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.23 (3H, s), 1.25-1.29 (1H,m), 1.34 (3H, s), 1.34-1.71 (9H, m), 1.77 (3H, brs), 1.80-1.90 (5H, m),2.01-2.12 (2H, m), 2.38-2.62 (7H, m), 2.66 (1H, dd, J=2.0, 7.6 Hz),2.86-2.97 (2H, m), 3.42-3.67 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.72(1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 63(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 63)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.09 (3H, t, J=7.2 Hz), 1.23(3H, s), 1.23-1.30 (1H, m), 1.34 (3H, s), 1.34-1.69 (7H, mil), 1.77 (3H,s), 1.83-1.92 (3H, m), 2.47-2.78 (10H, m), 2.89 (1H, dt, J=2.4, 6.4 Hz),3.44-3.68 (5H, m), 3.75-3.83 (1H, m), 4.94 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.58 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 665 (M+H)⁺.

Example 64(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 64)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 0.95 (3H, t, J=7.2 Hz), 1.23(3H, s), 1.23-1.30 (1H, m), 1.34 (3H, s), 1.30-1.69 (11H, m), 1.77 (3H,s), 1.86 (1H, dd, J=5.6, 14.0 Hz), 1.90-1.98 (2H, m), 2.47-2.62 (3H, m),2.62-2.73 (3H, m), 2.78-2.98 (5H, m), 3.44-3.73 (5H, m), 3.76-3.82 (1H,m), 4.95 (1H, d, J=10.4 Hz), 5.06 (1H, d, J=10.4 Hz), 5.58 (1H, dd,J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 693(M+H)⁺.

Example 65(8E,12E,14E)-7-((4-Cyclohexylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 65)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.06-1.69 (20H, m), 1.74-1.90(10H, m), 2.44-2.85 (9H, m), 2.89 (1H, dt, J=2.0, 5.6 Hz), 3.40-3.67(5H, m), 3.74-3.83 (1H, m), 4.94 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 719 (M+H)⁺.

Example 66(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-methyl-2-buten-1-yl)homopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 66)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.16-1.67 (14H, m), 1.67 (3H,s), 1.76 (3H, s), 1.77 (3H, s), 1.82-1.93 (3H, m), 2.44-2.80 (8H, m),2.89 (1H, dd, J=2.4, 5.6 Hz), 3.17 (2H, d, J=7.2 Hz), 3.43-3.70 (5H, m),3.72-3.83 (1H, m), 4.95 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4 Hz),5.20-5.30 (1H, m), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72 (1H, dd, J=10.0,15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H,dd, J=11.2, 15.2 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 67(8E,12E,14E)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 67)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.98-1.69 (14H, m), 1.77 (3H,s), 1.86 (1H, dd, J=6.0, 15.2 Hz), 2.33 (6H, s), 2.40-2.62 (11H, m),2.66 (11H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.4 Hz), 3.38-3.70(5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J=1.0 Hz), 5.06 (1H, d, J=10.4Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=10.0, 15.2 Hz),5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8,15.2 Hz); ESI-MS m/z 694 (M+H)⁺.

Example 68(8E,12E,14E)-7-((4-(2-(N,N-Diethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 68)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=60.5 Hz), 0.94 (3H, t, J=7.6 Hz), 1.08 (6H, t, J=7.2 Hz), 1.21(3H, s), 1.22-1.30 (1H, m), 1.34 (3H, s), 1.34-1.68 (7H, m), 1.77 (3H,s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.40-2.72 (16H, m), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.38-3.70 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J=9.6Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.71 (1H,dd, J=9.6, 15.2 Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz),6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 722 (M+H)⁺.

Example 69(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 69)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.85 (6H, s), 0.86 (3H, s),0.89 (3H, d, J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz),1.18-1.68 (14H, m), 1.72-1.82 (5H, m), 1.86 (1H, dd, J=5.6, 14.0 Hz),2.28 (2H, s), 2.46-2.62 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.68-2.75(2H, m), 2.81 (2H, dd, J=5.2, 10.4 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.36-3.68 (5H, m), 3.72-3.82 (1H, m), 4.94 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.57 (1H, dd, J=9.6, 14.8 Hz), 5.73 (1H, dd, J=9.6, 14.8Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 707 (M+H)⁺.

Example 70(8E,12E,14E)-7-((4-Cyclopentylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,11,14-trien-11-olide(Compound 70)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.18-1.68 (18H, m), 1.70-1.77(2H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.6, 14.0 Hz), 1.88-2.02 (4H, m),2.46-2.62 (3H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.82-3.02 (5H, m),3.08-3.22 (1H, m), 3.42-3.73 (5H, m), 3.73-3.84 (1H, m), 4.95 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.58 (1H, dd, J=9.6, 15.2 Hz), 5.73(1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 71(8E,12E,14E)-7-((4-Cyclopropylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 71)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400M Hz) δ(ppm): 0.34-0.52 (4H, m), 0.89 (3H, d,J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.13-1.70(15H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.35-2.72 (8H,m), 2.80-2.92 (1H, m), 3.30-3.68 (5H, m), 3.70-3.82 (1H, m), 4.92 (1H,d, J=10.0 Hz), 5.05 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz),5.70 (1H, dd, J=9.6, 15.2 Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 663 (M+H)⁺, 685(M+Na)⁺.

Example 72(8E,12E,14E)-7-((4-(1,1-Dimethylethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 72)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.10 (9H, s), 1.22 (3H, s),1.22-1.30 (1H, m), 1.34 (3H, s), 1.35-1.69 (7H, m), 1.77 (3H, s), 1.86(1H, dd, J=5.2, 14.0 Hz), 2.50-2.64 (7H, m), 2.67 (1H, dd, J=9.4, 8.0Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.38-3.68 (5H, m), 3.74-3.82 (1H, m),4.93 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=9.6,15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 679(M+H)⁺.

Example 73(8E,12E,14E)-7-((4-Cyclopropylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 73)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.32-0.54 (4H, m), 0.89 (3H, d,J=6.8 Hz), 0.90 (3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.14-1.68(15H, m), 1.69-1.93 (6H, m), 2.42-2.62 (3H, m), 2.66 (1H, dd, J=2.4, 8.0Hz), 2.70-2.92 (5H, m), 3.38-3.68 (5H, m), 3.68-3.82 (1H, m), 4.94 (1H,d, J=10.4 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz),5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d,J=11.2 Hz), 6.52 (1H, dd, J=1.2, 15.2 Hz); ESI-MS m/z 677 (M+H)⁺.

Example 74(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 74)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.87-0.92 (15H, m), 0.94 (3H, t,J=7.6 Hz), 1.20-1.29 (4H, m), 1.31-1.69 (10H, m), 1.77 (3H, d, J=1.2Hz), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.09 (2H, s), 2.45-2.64 (7H, m),2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.36-3.67(5H, m), 3.75-3.83 (1H, m), 4.92 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.6, 10.8 Hz), 6.53 (1H, dd, J=10.8,15.2 Hz); ESI-MS m/z 693 (M+H)⁺.

Example 75(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 75)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.06 (6H, brt, J=7.0 Hz),1.15-1.65 (7H, m), 1.22 (3H, brs), 1.33 (3H, s), 1.65 (1H, dd, J=6.2,14.3H), 1.77 (3H, s), 1.86 (1H, dd, J=6.2, 14.3 Hz), 2.46-2.65 (5H, m),2.59 (4H, q, J=7.0 Hz), 2.66 (1H, dd, J=2.2, 8.1 Hz), 2.89 (1H, dt,J=2.2, 6.2 Hz), 2.92 (1.6H, s), 2.99 (1.4H, s), 3.28-3.40 (1H, m), 3.52(1H, dt, J=4.0, 8.4 Hz), 3.52-3.62 (1H, m), 3.74-3.81 (1H, m), 4.92 (1H,d, J=9.5 Hz), 5.06 (1H, d, J=10.6 Hz), 5.56 (1H, dd, J=9.9, 15.0 Hz),5.72 (1H, dd, J=9.5, 15.0 Hz), 5.86 (1H, d, J=15.4 Hz), 6.13 (1H, d,J=10.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz); ESI-MS m/z 667 (M+H)⁺.

Example 76(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 76)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.888 (3H, d, J=6.6 Hz), 0.894(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.19-1.65 (7H, m), 1.22 (3H,s), 1.33 (3H, s), 1.65 (1H, dd, J=6.6, 13.9 Hz), 1.77 (3H, d, J=0.7 Hz),1.86 (1H, dd, J=6.2, 13.9 Hz), 2.45-2.61 (9H, m), 2.66 (1H, dd, J=2.6,7.7 Hz), 2.89 (1H, dt, J=2.6, 6.2 Hz), 2.91 (1.6H, s), 2.98 (1.4H, s),3.30-3.45 (1H, m), 3.52 (1H, dt, J=4.4, 8.1 Hz), 3.60-3.71 (5H, m),3.74-3.81 (1H, m), 4.92 (1H, d, J=9.9 Hz), 5.06 (1H, d, J=10.6 Hz),5.51-5.60 (1H, m), 5.67-5.77 (1H, m), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H,d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 681 (M+H)⁺.

Example 77(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 77)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.0 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.19-1.68 (17H, m), 1.33 (3H,s), 1.77 (3H, d, J=0.7 Hz), 1.86 (1H, dd, J=5.5, 13.9 Hz), 2.41-2.62(9H, m), 2.66 (1H, dd, J=2.6, 7.7 Hz), 2.87-2.92 (1H, m), 2.90 (1.6H,s), 2.98 (1.4H, s), 3.36-3.45 (1H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz),3.55-3.62 (1H, m), 3.74-3.81 (1H, m), 4.86-4.93 (1H, m), 5.05 (1H, d,J=10.6 Hz), 5.56 (1H, dd, J=9.9, 15.0 Hz), 5.71 (1H, dd, J=10.6, 15.0Hz), 5.86 (1H, d, J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, dd,J=11.0, 15.4 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 78(8E,12E,14E)-7-(N-Ethyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 78)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.886 (3H, d, J=6.6 Hz), 0.893(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.08-1.17 (3H, m), 1.18-1.65(7H, m), 1.22 (3H, s), 1.33 (3H, s), 1.65 (1H, dd, J=5.5, 13.9 Hz), 1.77(3H, d, J=1.1 Hz), 1.86 (1H, dd, J=5.5, 13.9 Hz), 2.44-2.62 (9H, m),2.66 (1H, dd, J=9.2, 8.1 Hz), 2.89 (1H, dt, J=2.2, 5.5 Hz), 3.30-3.54(3H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz), 3.54-3.71 (5H, m), 3.73-3.81 (1H,m), 4.92 (1H, brd, J=9.5 Hz), 5.06 (1H, d, J=10.6 Hz), 5.57 (1H, dd,J=9.9, 15.0 Hz), 5.67-5.78 (1H, m), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H,d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 695 (M+H)⁺.

Example 79(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 79)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.19-1.65 (10H, m), 1.33 (3H,s), 1.65 (1H, dd, J=5.5, 14.3 Hz), 1.74-1.85 (4H, m), 1.77 (3H, s), 1.86(1H, dd, J=5.5, 14.3 Hz), 2.49-2.68 (10H, m), 2.86-2.92 (1H, m), 2.91(1.6H, s), 2.99 (1.4H, s), 3.39-3.60 (2H, m), 3.52 (1H, dt, J=4.4, 8.4Hz), 3.73-3.81 (1H, m), 4.91 (1H, d, J=9.5 Hz), 5.05 (1H, d, J=10.6 Hz),5.56 (1H, dd, J=9.9, 15.4 Hz), 5.72 (1H, dd, J=9.5, 15.4 Hz), 5.86 (1H,d, J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz);ESI-MS m/z 665 (M+H)⁺.

Example 80(8E,12E,14E)-7-(N-(3-(N′,N′-Diethylamino)propyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 80)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.05 (6H, t, J=7.3 Hz),1.21-1.81 (10H, m), 1.21 (3H, s), 1.33 (3H, s), 1.77 (3H, s), 1.86 (1H,dd, J=5.5, 13.6 Hz), 2.46-2.62 (5H, m), 2.58 (4H, q, J=7.3 Hz), 2.66(1H, dd, J=2.2, 8.1 Hz), 2.87-2.95 (1H, m), 2.89 (1.6H, s), 2.97 (1.4H,s), 3.20-3.32 (1H, m), 3.50-3.59 (1H, m), 3.52 (1H, dt, J=4.4, 8.4 Hz),3.74-3.82 (1H, m), 4.93 (1H, d, J=9.9 Hz), 5.06 (1H, d, J=10.6 Hz), 5.56(1H, dd, J=9.9, 15.0 Hz), 5.73 (1H, dd, J=9.9, 15.0 Hz), 5.86 (1H, d,J=15.4 Hz), 6.13 (1H, d, J=11.0 Hz), 6.52 (1H, dd, J=11.0, 15.4 Hz);ESI-MS m/z 681 (M+H)⁺.

Example 81(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 81)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 3.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.6 Hz), 0.89(3H, d, J=7.0 Hz), 0.93 (3H, t, J=7.3 Hz), 1.19-1.70 (7H, m), 1.20(1.2H, s), 1.22 (1.8H, s), 1.33 (3H, s), 1.65 (1H, dd, J=6.2, 14.3 Hz),1.72-1.77 (1H, m), 1.77 (3H, d, J=0.7 Hz), 1.86 (1H, dd, J=6.2, 14.3Hz), 1.86-1.92 (1H, m), 2.38 (1.21H, s), 2.40 (1.8H, s), 2.50-2.62 (3H,m), 2.63-2.70 (2H, m), 2.74-2.83 (1H, m), 2.89 (1H, dt, J=2.2, 6.2 Hz),3.21 (0.6H, dd, J=1.8, 10.6 Hz), 3.36 (0.4H, dd, J=1.8, 10.6 Hz),3.47-3.59 (3H, in), 3.75-3.82 (1H, m), 4.32 (0.4H, s), 4.55 (0.6H, s),4.91 (1H, d, J=9.9 Hz), 5.06 (1H, d, J=10.6 Hz), 5.68-5.77 (1H, m),5.51-5.61 (1H, m), 5.86 (1H, d, J=15.0 Hz), 6.13 (1H, d, J=11.0 Hz),6.52 (1H, dd, J=11.0, 15.0 Hz); ESI-MS m/z 649 (M+H)⁺.

Example 82(8E,12E,14E)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 82)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.93 (3H, d, J=6.8 Hz), 0.94(3H, d, J=6.8 Hz), 0.98 (3H, t, J=7.2 Hz), 1.10-1.18 (3H, m), 1.22-1.74(14H, m), 1.80 (1H, brs), 1.82 (3H, s) 1.87-1.95 (2H, m), 2.51-2.77 (7H,m), 2.87-2.97 (2H, m), 3.23-3.29 (0.5H, m), 3.37-3.43 (0.51H, m),3.51-3.63 (2H, m), 3.63-3.69 (1H, m), 3.79-3.87 (1H, m), 4.37 (0.5H,brs), 4.60 (0.5H, brs), 4.96 (H1H, d, J=9.6 Hz), 5.11 (1H, d, J=10.4Hz), 5.57-5.67 (1H, m), 5.72-5.67 (1H, m), 5.91 (1H, d, J=15.2 Hz), 6.18(1H, d, J=11.2 Hz), 6.57 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 663(M+H)⁺.

Example 83(8E,12E,14E)-7-((4-Cyclooctylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 83)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.94 (3H, d, J=6.8 Hz), 0.94(3H, d, J=6.8 Hz), 0.98 (3H, t, J=7.2 Hz), 1.25 (3H, s), 1.25-1.87 (28H,m), 1.91 (1H, dd, J=5.6, 14.4 Hz), 2.50-2.76 (9H, m), 2.93 (1H, dt,J=2.0, 6.0 Hz), 3.42-3.74 (5H, m), 3.78-3.88 (1H, m), 4.97 (1H, d, J=9.6Hz), 5.11 (1H, d, J=10.4 Hz), 5.61 (1H, dd, J=9.6, 15.2 Hz), 5.76 (1H,dd, J=9.6, 15.2 Hz), 5.91 (1H, d, J=15.2 Hz), 6.18 (1H, d, J=11.2 Hz),6.57 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 733 (M+H)⁺.

Example 84(8E,12E,14E)-7-((4-(Ethoxycarbonylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 84)

The title compound (a colorless oil) was synthesized by a similar methodas described for Examples 46 and 47.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.20-1.42 (3H, m), 1.21 (3H,s), 1.26 (3H, t, J=7.2 Hz), 1.34 (3H, s), 1.44-1.54 (2H, m), 1.56-1.64(2H, m), 1.65 (1H, dd, J=6.5, 14.4 Hz), 1.78 (3H, s), 1.86 (1H, dd,J=5.0, 14.4 Hz), 2.50-2.62 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz),2.87-2.91 (1H, m), 3.26 (2H, s), 3.40-3.70 (4H, m), 3.50-3.55 (1H, m),3.75-3.81 (1H, m), 4.17 (2H, q, J=7.2 Hz), 4.93 (1H, d, J=10.0 Hz), 5.06(1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H, dd, J=9.8,15.2 Hz) 5.87 (1H, d, J=15.6 Hz), 6.13 (1H, d, J=10.0 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 731 (M+Na)⁺.

Example 85(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85)

First Step

(8E,12E,14E)-7-Acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85-1)

To a solution of Compound 46-1(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(171 mg, 0.19 mmol) obtained in the first step of Example 46 in toluene(6 mL) were added methyl trifluoromethanesulfonate (188 mg, 1.14 mmol)and 1,8-bis(N,N-dimethylamino)naphthalene (368 mg, 1.71 mmol) at roomtemperature, and the reaction mixture was stirred at 65° C. for 14hours. Further, methyl trifluoromethanesulfonate (304 mg, 119 mmol) and1,8-bis(N,N-dimethylamino)naphthalene (400 mg, 1.9 mmol) were added tothis mixture at room temperature, and the reaction mixture was stirredat 65° C. for 6 hours. The reaction mixture was diluted with diethylether and was filtrated through a glass filter. The filtrate was mixedwith 28% aqueous ammonia (1 mL), and the reaction mixture was stirred atroom temperature for one hour and sequentially washed with brine, a 0.1Maqueous solution of citric acid, a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N,40-100 μm; ethyl acetate:hexane=10:90) to give the title compound (141mg, 84%) as a colorless oil.

ESI-MS m/z 932 (M+Na)⁺.

Second Step

(8E,12E,14E)-7-Hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85-2)

To a solution of Compound 85-1(8E,12E,14E)-7-acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(158 mg, 0.17 mmol) obtained in the first step in methanol (5 mL) wasadded potassium carbonate (120 mg, 0.87 mmol) at room temperature, thenthe reaction mixture was stirred at the same temperature for threehours. The reaction mixture was diluted with ethyl acetate and washedwith brine. The organic layer was dried over anhydrous magnesium sulfateand concentrated. The crude product was purified by silica gel columnchromatography (Kanto silica gel 60N, 40-100 μm; ethylacetate:hexane=10:90) to give the title compound (91 mg, 61%) as acolorless oil.

ESI-MS m/z 890 (M+Na)⁺.

Third Step

(8E,12E,14E)-6-Methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85-3)

To a solution of Compound 85-2(8E,12E,14E)-7-hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(91 mg, 0.11 mmol) obtained in the second step in dichloromethane (4 mL)were added triethylamine (64 mg, 0.52 mmol), N,N-dimethylaminopyridine(64 mg, 0.52 mmol) and 4-nitrophenyl chloroformate (63 mg, 0.31 mmol) atroom temperature, and the reaction mixture was stirred at the sametemperature for 2.5 hours. The reaction mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodiumbicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate and concentrated. The resulting residue was purifiedby silica gel column chromatography (Kanto silica gel 60N, 40-100 μm;ethyl acetate:hexane=10:90) to give the title compound (97 mg, 89%) as acolorless oil.

ESI-MS m/z 1055 (M+Na)⁺.

Fourth Step

(8E,12E,14E)-6-Methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85-4)

To a solution of Compound 85-3(8E,12E,14E)-6-methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(30 mg, 29 μmol) obtained in the third step in tetrahydrofuran (2 mL)were added triethylamine (11 mg, 0.12 mmol) and 1-methylpiperazine (5.8mg, 58 μmol) at room temperature, and the reaction mixture was stirredat the same temperature for one hour. The reaction mixture was dilutedwith ethyl acetate and washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N,40-100 μm; methanol:dichloromethane=3:97) to give the title compound (26mg, 89%) as a colorless oil.

ESI-MS m/z 994 (M+H)⁺.

Fifth Step

(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 85)

To a solution of Compound 85-4(8E,12E,14E)-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(25 mg, 25 μmol) obtained in the fourth step in tetrahydrofuran (3 mL)was added tetrabutylammonium fluoride (83 μl, 1.0 M tetrahydrofuransolution) at room temperature, then the reaction mixture was stirred atthe same temperature for 1.5 hours. The reaction mixture was dilutedwith ethyl acetate and washed with a saturated aqueous solution ofsodium bicarbonate and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtrated and concentrated. The resulting residue waspurified by thin layer chromatography (Fuji Silysia, NH Silica gelPlate; methanol:dichloromethane=5:95) to give the title compound (11 mg,67%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.21 (3H, s), 1.34 (3H, s),1.22-1.69 (8H, m), 1.78 (3H, s), 1.86 (1H, dd, J=5.6, 14.0 Hz), 2.29(3H, s), 2.36-2.44 (4H, m), 2.45-2.60 (3H, m), 2.67 (1H, dd, J=2.4, 8.0Hz), 2.86-2.92 (1H, m), 3.34 (3H, s), 3.44-3.58 (5H, m), 3.78-3.86 (1H,m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=11.2 Hz), 5.56 (1H, dd,J=9.6, 15.2 Hz), 5.73 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=9.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z651 (M+H)⁺.

Example 86(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 86)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.22-1.82 (8H,m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J=6.0, 14.0 Hz), 2.44-2.62(3H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.70-2.82 (4H, m), 2.89 (1H, dt,J=2.4, 5.6 Hz) 3.25-3.36 (3H, covered with CD₃OD), 3.38-3.55 (5H, m),3.78-3.86 (1H, m), 5.02 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57(1H, dd, J=9.6, 15.6 Hz), 5.73 (1H, dd, J=9.6, 15.6 Hz), 5.86 (1H, d,J=15.6 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.6 Hz);ESI-MS m/z 637 (M+H)⁺.

Example 87(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)carbamoyloxy)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 87)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.06 (6H, t, J=7.2 Hz), 1.22(3H, s), 1.22-1.70 (8H, m), 1.34 (3H, s), 1.78 (3H, s), 1.86 (1H, dd,J=5.2, 14.0 Hz), 2.44-2.64 (9H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89(1H, dt, J=2.4, 6.0 Hz), 3.21 (2H, t, J=7.2 Hz) 3.25-3.36 (3H, coveredwith CD₃OD), 3.48-3.56 (1H, m), 3.77-3.85 (1H, m), 4.97 (1H, d, J=9.6Hz), 5.06 (1H, d, J=10.5 Hz), 5.54 (1H, dd, J=10.0, 15.2 Hz), 5.71 (1H,dd, J=9.6, 15.6 Hz), 5.86 (1H, d, J=15.6 Hz), 6.13 (1H, d, J=10.8 Hz),6.52 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z 667 (M+H)⁺.

Example 88(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 88)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.17-1.69 (6H, m), 1.72-1.90(6H, m), 2.10-2.26 (2H, m), 2.33 (3H, s), 2.44-2.62 (3H, m), 2.66 (1H,dd, J=2.4, 8.0 Hz), 2.82 (3H, s), 2.89 (1H, dt, J=2.4, 6.0 Hz),2.95-3.03 (2H, m), 3.35 (3H, s), 3.52 (1H, dt, J=4.4, 8.0 Hz), 3.78-3.85(1H, m), 3.92-4.04 (1H, m), 5.03 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.5 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 679 (M+H)⁺.

Example 89(8E,12E,14E)-7-((4-(N,N-Dimethylamino)piperidin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 89)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.17-1.68 (6H, m), 1.78 (3H,s), 1.81-1.94 (3H, m), 2.29 (6H, s), 2.34-2.63 (4H, m), 2.67 (1H, dd,J=2.4, 8.0 Hz), 2.73-2.89 (2H, m), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.33(3H, s), 3.52 (1H, dt, J=4.4, 7.6 Hz), 3.78-3.85 (1H, m), 4.10-4.30 (2H,m), 5.01 (1H, d, J=9.2 Hz), 5.06 (1H, d, J=10.8 Hz), 5.56 (1H, dd,J=10.0, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.88 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MSm/z 679 (M+H)⁺.

Example 90(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 90)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.84-0.92 (9H, m), 0.94 (3H, t,J=7.2 Hz), 0.24 (3H, s), 1.34 (3H, s), 1.22-1.69 (10H, m), 1.78 (3H, d,J=0.8 Hz), 1.82-1.90 (3H, m), 2.40-2.72 (10H, m), 2.89 (1H, dt, J=2.0,6.0 Hz), 3.24-3.36 (3H, covered with CD₃OD), 3.44-3.60 (5H, m),3.78-3.86 (1H, m), 5.03 (1H, d, J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.56(1H, dd, J=9.6, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d,J=15.6 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.6 Hz);ESI-MS m/z 693 (M+H)⁺.

Example 91(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 91)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.86-0.98 (12H, m), 1.23 (3H,brs), 1.34 (3H, s), 1.22-1.70 (12H, m), 1.78 (3H, d, J=0.8 Hz) 1.82-1.89(3H, m), 2.44-2.74 (10H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.30 (3H, s),3.42-3.58 (5H, m), 3.79-3.85 (1H, m), 5.03 (1H, d, J=9.2 Hz), 5.07 (1H,d, J=10.4 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 707 (M+H)⁺.

Example 92(8E,12E,14E)-7-((4-Cyclopropylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 92)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.38-0.42 (2H, m), 0.47-0.52(2H, m), 1.88 (3H, d, J=6.4 Hz), 0.90 (3H, d, J=7.2 Hz), 0.94 (3H, t,J=7.2 Hz), 1.23 (3H, s), 1.34 (3H, s), 1.22-1.68 (9H, m), 1.78 (3H, d,J=0.8 Hz), 1.80-1.92 (3H, m), 2.44-2.60 (3H, m), 2.66 (1H, dd, J=2.0,7.6 Hz), 2.74-2.87 (4H, m), 2.89 (1H, dt, J=10.6, 5.6 Hz), 3.33 (3H, s),3.44-3.60 (5H, m), 3.78-3.86 (1H, m), 5.03 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.4 Hz), 5.56 (1H, dd, J=10.0, 15.6 Hz), 5.74 (1H, dd, J=10.0,15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H,dd, J=11.2, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 93(8E,12E,14E)-7-((4-Cyclobutylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 93)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.23 (3H, s), 1.34 (3H, s),1.22-1.72 (10H, m), 1.78 (3H, s), 1.80-1.90 (5H, m), 2.02-2.10 (2H, m),2.41-2.60 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.86-2.94 (2H, m),3.24-3.36 (3H, covered with CD₃OD), 3.44-3.60 (5H, m), 3.78-3.86 (1H,m), 5.03 (1H, dd, J=2.0, 9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.56 (1H, dd,J=10.0, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.2Hz), 6.14 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z705 (M+H)⁺.

Example 94(8E,12E,14E)-7-((4-Cyclopentylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 94)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.23 (3H, s), 1.34 (3H, s),1.36-1.72 (16H, m), 1.78 (3H, d, J=0.8 Hz), 1.82-1.90 (3H, m), 2.44-2.60(3H, m), 2.64-2.70 (3H, m), 2.73-2.82 (2H, m), 2.84-2.94 (2H, m),3.24-3.36 (3H, covered with CD₃OD), 3.44-3.60 (5H, m), 3.78-3.86 (1H,m), 5.04 (1H, d, J=11.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.56 (1H, dd,J=9.6, 15.6 Hz), 5.74 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z719 (M+H)⁺.

Example 95(8E,12E,14E)-7-((4-Cyclohexylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 95)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.23 (3H, s), 1.34 (3H, s),1.12-1.68 (18H, m), 1.78 (3H, d, J=0.8 Hz), 1.75-1.89 (3H, m), 2.42-2.60(4H, m), 2.64-2.72 (3H, m), 2.75-2.82 (2H, m), 2.89 (1H, dt, J=1.2, 5.2Hz), 3.26-3.36 (3H, covered with CD₃OD), 3.42-3.56 (5H, m), 3.78-3.86(1H, m), 5.03 (1H, dd, J=3.2, 9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.56(1H, dd, J=10.0, 15.2 Hz), 5.74 (1H, dd, J=10.0, 14.8 Hz), 5.87 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 733 (M+H)⁺.

Example 96(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isopropylhomopiperazin-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 96)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.03 (6H, d, J=6.4 Hz), 1.24(3H, s), 1.34 (3H, s), 1.22-1.69 (8H, m), 1.78 (3H, s), 1.76-1.90 (3H,m), 2.44-2.74 (8H, m), 2.86-2.94 (2H, m), 3.33 (3H, s), 3.44-3.60 (5H,m), 3.79-3.86 (1H, m), 5.03 (1H, dd, J=4.4, 9.6 Hz), 5.07 (1H, d, J=10.8Hz), 5.56 (1H, dd, J=10.8, 16.0 Hz), 5.74 (1H, dd, J=9.6, 15.6 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.6 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 693 (M+H)⁺.

Example 97(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 97)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.84-0.95 (15H, m), 1.26 (3H,s), 1.34 (3H, s), 1.22-1.76 (9H, m), 1.78 (3H, s), 1.78-1.90 (3H, m),2.23 (2H, d, J=6.8 Hz), 2.44-2.72 (8H, m), 2.89 (1H, dt, J=2.0, 5.2 Hz),3.24-3.38 (3H, covered with CD₃OD), 3.42-3.58 (5H, m), 3.78-3.86 (1H,m), 5.03 (1H, d, J=9.6 Hz), 5.07 (1H, d, J=10.4 Hz), 5.56 (1H, dd,J=9.6, 15.2 Hz), 5.74 (1H, dd, J=9.2, 14.8 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 707(M+H)⁺.

Example 98(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(morpholin-4-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 98)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.88 (3H, d, J=5.2 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.34 (3H, s),1.24-1.68 (10H, m), 1.78 (3H, d, J=1.2 Hz), 1.82-1.96 (3H, m), 2.32-2.43(1H, m), 2.44-2.62 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.74-2.92 (3H,m), 3.32 (3H, s), 3.52 (1H, dt, J=3.6, 8.0 Hz), 3.64-3.74 (4H, m),3.78-3.86 (1H, m), 4.08-4.28 (2H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.54 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 721 (M+H)⁺.

Example 99(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 99)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=5.6 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.34 (3H, s),1.23-1.70 (10H, m), 1.78 (3H, s), 1.79-1.90 (5H, m), 1.92-2.00 (2H, m),2.20-2.30 (1H, m), 2.44-2.68 (8H, m), 2.76-2.92 (3H, m), 3.24-3.36 (3H,covered with CD₃OD), 3.52 (1H, dt, J=4.8, 8.0 Hz), 3.77-3.86 (1H, in),4.04-4.24 (2H, m), 5.01 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4 Hz),5.56 (T H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H,d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 705 (M+H)⁺.

Example 100(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-(4-hydroxypiperidin-1-yl)piperidin-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 100)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.21 (3H, s), 1.34 (3H, s),1.22-1.69 (12H, m), 1.78 (3H, s), 1.82-1.93 (5H, m), 2.28-2.38 (2H, m),2.43-2.58 (4H, m), 2.67 (1H, dd, J=2.0, 7.6 Hz), 2.72-2.83 (5H, m),3.24-3.39 (3H, covered with CD₃OD), 3.52 (1H, dt, J=4.8, 8.0 Hz),3.56-3.64 (1H, m), 3.78-3.86 (1H, m), 4.10-4.30 (2H, m), 5.00 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.55 (1H, dd, J=10.4, 15.2 Hz), 5.73(1H, dd, J=10.0, 15.6 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 735 (M+H)⁺.

Example 101(8E,12E,14E)-7-(N-(3-(N′,N′-Dimethylamino)propyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 101)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.34 (3H, s),1.20-1.78 (10H, m), 1.78 (3H, s), 1.86 (1H, dd, J=6.3, 14.5 Hz), 2.24(6H, s), 2.31 (2H, t, J=8.8 Hz), 2.44-2.60 (3H, m), 2.66 (1H, dd, J=2.4,8.0 Hz), 2.85-2.96 (4H, m), 3.22-3.38 (5H, covered with CD₃OD), 3.52(1H, dd, J=3.6, 8.0 Hz), 3.78-3.85 (1H, m), 5.01 (1H, d, J=10.0 Hz),5.06 (1H, d, J=10.4 Hz), 5.55 (1H, dd, J=9.6, 15.2 Hz), 5.74 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=1.8 Hz), 6.53(1H, dd, J11.2, 15.2 Hz); ESI-MS m/z 667 (M+H)⁺.

Example 102(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholin-4-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 102)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.22 (3H, s), 1.34 (3H, s),1.23-1.69 (8H, m), 1.78 (3H, s), 1.86 (1H, dd, J=4.6, 12.7 Hz),2.44-2.56 (9H, m), 2.66 (1H, dd, J=2.4, 7.6 Hz), 2.86-2.96 (4H, m),3.22-3.38 (2H, covered with CD₃OD), 3.34 (3H, s), 3.52 (1H, dt, J=4.0,8.0 Hz), 3.62-3.72 (4H, m), 3.78-3.84 (1H, m), 5.01 (1H, d, J=10.0 Hz),5.06 (1H, d, J=10.8 Hz), 5.55 (1H, dd, J=10.0, 15.2 Hz), 5.68-5.79 (1H,m), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.4 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 695 (M+H)⁺.

Example 103(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbamoyloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 103)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.22 (3H, s), 1.34 (3H, s),1.23-1.68 (8H, m), 1.78 (3H, d, J=0.8 Hz), 1.78-1.83 (4H, m), 1.86 (1H,dd, J=5.4, 13.1 Hz), 2.44-2.68 (10H, m), 2.86-2.97 (4H, m), 3.34 (3H,s), 3.40-3.48 (2H, m), 3.52 (1H, dt, J=4.0, 7.6 Hz), 3.78-3.86 (1H, m),5.00 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.55 (1H, dd, J=10.0,14.8 Hz), 5.74 (1H, dd, J=9.6, 14.8 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 679(M+H)⁺.

Example 104(8E,12E,14E)-7-(N-(3-(N′,N′-Eiethylamino)propyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 104)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.05 (6H, t, J=7.2 Hz), 1.22(3H, s), 1.34 (3H, s), 1.20-1.82 (10H, m), 1.78 (3H, s), 1.86 (1H, dd,J=5.6, 14.4 Hz), 2.42-2.60 (9H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz),2.84-2.96 (4H, m), 3.22-3.40 (5H, covered with CD₃OD), 3.52 (1H, dt,J=3.6, 8.0 Hz), 3.78-3.86 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d,J=10.4 Hz), 5.55 (1H, dd, J=10.0, 15.6 Hz), 5.74 (1H, dd, J=9.6, 15.6Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.0 Hz), 6.53 (1H, dd,J=11.2, 15.2 Hz); ESI-MS m/z 695 (M+H)⁺.

Example 105(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 105)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.38-1.69 (7H, m), 1.78 (3H, d, J=0.8 Hz), 1.83-1.93 (3H, m), 2.35(3H, s), 2.45-2.65 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.4, 6.0 Hz), 3.32 (1.5H, s), 3.33 (1.5H, s), 3.46-3.62 (5H, m),3.79-3.86 (1H, m), 5.01-5.06 (1H, m), 5.07 (1H, d, J=10.4 Hz), 5.56 (1H,dd, J=9.6, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, dd, J=1.2, 11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 665 (M+H)⁺.

Example 106(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 106)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.11 (3H, t, J=7.6 Hz),1.20-1.29 (4H, m), 1.34 (3H, s), 1.37-1.69 (7H, m), 1.78 (3H, d, J=0.8Hz), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.41-2.63 (9H, m), 2.67 (1H, dd,J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.32 (3H, s), 3.43-3.59(5H, m), 3.79-3.86 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8Hz), 5.56 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H, dd, J=10.8,15.2 Hz); ESI-MS m/z 665 (M+H)⁺.

Example 107(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 107)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.08 (3H, t, J=7.2 Hz),1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.70 (7H, m), 1.78 (3H, d, J=0.8Hz), 1.82-1.90 (3H, m), 2.45-2.73 (10H, m), 2.89 (1H, dt, J=2.4, 6.0Hz), 3.33 (1.5H, s), 3.33 (1.5 Hs), 3.46-3.62 (5H, m), 3.79-3.85 (1H,m), 5.00-5.06 (1H, m), 5.07 (1H, d, J=10.8 Hz), 5.56 (1H, dd, J=10.0,15.2 Hz), 5.74 (1H, dd, J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13(1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 679(M+H)⁺.

Example 108(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 108)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.38-1.70 (7H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0Hz), 2.27 (6H, s), 2.45-2.63 (5H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz),2.87-2.97 (4H, m), 3.30-3.36 (3H, m), 3.37-3.46 (2H, m), 3.52 (1H, td,J=4.4, 8.0 Hz), 3.78-3.85 (1H, m), 5.00 (1H, d, J=9.6 Hz), 5.06 (1H, d,J=10.4 Hz), 5.55 (1H, dd, J=9.6, 15.2 Hz), 5.69-5.79 (1H, m), 5.87 (1H,d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 653 (M+H)⁺.

Example 109(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 109)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.31-1.69(18H, m), 1.78 (3H, s), 1.83-1.93 (3H, m), 2.41-2.61 (8H, m), 2.67 (1H,dd, J=2.4, 8.0 Hz), 2.70-2.88 (2H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.33 (3H, s), 3.52 (1H, td, J=4.4, 8.0 Hz), 3.78-3.85 (1H, m), 4.11-4.29(2H, m), 5.00 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.56 (1H, dd,J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 719(M+H)⁺.

Example 110(8E,12E,14E)-3,16,21-Trihydroxy-7-(4-(isopropylpiperazin-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 110)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.7 Hz), 1.07 (6H, d, J=6.8 Hz),1.20-1.29 (4H, m), 1.32-1.76 (10H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H,dd, J=5.6, 14.0 Hz), 2.45-2.63 (7H, m), 2.64-2.75 (2H, m), 2.89 (1H, dt,J=2.4, 6.0 Hz), 3.32 (3H, s), 3.42-3.59 (5H, m), 3.78-3.86 (1H, m), 5.01(1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.56 (1H, dd, J=9.6, 15.2Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H,d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 111(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound III)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.93 (3H, t, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz),1.20-1.30 (4H, m), 1.34 (3H, s), 1.39-1.69 (9H, m), 1.78 (3H, d, j=1.2Hz), 1.87 (1H, dd, J=5.2, 14.0 Hz), 2.31-2.37 (2H, m), 2.40-2.63 (7H,m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.90 (1H, dt, J=2.0, 6.0 Hz), 3.32(3H, s), 3.42-3.60 (5H, m), 3.79-3.86 (1H, m), 5.02 (1H, d, J=9.6 Hz),5.07 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.74 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.14 (1H, d, J=11.2 Hz), 6.53(1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 112(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 112)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz),1.19-1.29 (4H, m), 1.29-1.69 (14H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H,dd, J=5.2, 14.0 Hz), 2.34-2.39 (2H, m), 2.40-2.63 (7H, m), 2.67 (1H, dd,J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.32 (3H, s), 3.41-3.60(5H, m), 3.79-3.85 (1H, m), 5.01 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 693 (M+H)⁺.

Example 113(8E,12E,14E)-3,16,21-Trihydroxy-7-((4-isobutylpiperazin-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 113)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.91 (6H, d, J=6.4 Hz), 0.94 (3H, t, J=7.6 Hz),1.19-1.29 (4H, m), 1.34 (3H, s), 1.39-1.69 (7H, m), 1.76-1.90 (5H, m),2.11 (2H, d, J=7.2 Hz), 2.33-2.41 (4H, m), 2.45-2.63 (3H, m), 2.67 (1H,dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.32 (3H, s),3.40-3.58 (5H, m), 3.79-3.86 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 693 (M+H)⁺.

Example 114(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-7-((4-(2-methoxyethyl)piperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 114)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400M Hz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.38-1.69 (7H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.6, 14.0Hz), 2.44-2.63 (9H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.32 (3H, s), 3.33 (3H, s), 3.41-3.59 (7H, m), 3.78-3.85(1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.56 (1H, dd,J=−0.0, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z695 (M+H)⁺.

Example 115(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(tetrahydropyran-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 115)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.38-1.69 (9H, m), 1.77-1.85 (5H, m), 1.86 (1H, dd, J=5.2, 14.0 Hz),2.43-2.63 (8H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4,6.0 Hz), 3.32 (3H, s), 3.35-3.43 (2H, m), 3.43-3.59 (5H, m), 3.78-3.85(1H, m), 3.98 (2H, dd, J=4.4, 11.2 Hz), 5.01 (1H, d, J=10.0 Hz), 5.06(1H, d, J=10.4 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=9.6,15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 11.2 Hz), 6.53(1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 721 (M+H)⁺.

Example 116(8E,12E,14E)-7-((4-Cyclopropylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 116)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NM Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.40-0.46 (2H, m), 0.46-0.53(2H, m), 0.89 (3H, d, J=6.4 Hz), 0.90 (3H, d, J=6.8 Hz), 0.94 (3H, t,J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.70 (8H, m), 1.78 (3H,d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.45-2.63 (7H, m), 2.67(1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.32 (3H, s),3.37-3.56 (5H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H,d, J=10.8 Hz), 5.56 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=10.0, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H,dd, J=10.8, 15.2 Hz); ESI-MS m/z 677 (M+H)⁺.

Example 117(8E,12E,14E)-7-((4-Cyclobutylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 117)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.39-1.78 (9H, m), 1.78 (3H, d, J=0.8 Hz), 1.83-1.95 (3H, m),2.02-2.10 (2H, m), 2.31 (4H, t, J=4.8 Hz), 2.45-2.63 (3H, m), 2.67 (1H,dd, J=2.4, 8.0 Hz), 2.72-2.81 (1H, m), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.31 (3H, s), 3.40-3.58 (5H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J=9.6Hz), 5.06 (1H, d, J=10.8 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H,dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz),6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 118(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 118)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.36-1.77 (13H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2,14.0 Hz), 1.86-1.95 (2H, m), 2.44-2.63 (8H, m), 2.67 (1H, dd, J=2.4, 8.0Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.32 (3H, s), 3.42-3.59 (5H, m),3.78-3.85 (1H, m), 5.01 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.4 Hz),5.56 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H,d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2Hz); ESI-MS m/z 705 (M+H)⁺.

Example 119(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 119)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90 (3Hd, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.09-1.33 (10H, m), 1.34 (3H, s),1.39-1.69 (7H, m), 1.78 (3H, d, J=0.8 Hz) 1.78-1.93 (5H, m), 2.27-2.35(1H, m), 2.45-2.65 (7H, m), 2.67 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.4, 6.0 Hz), 3.32 (3H, s), 3.39-3.58 (5H, m), 3.79-3.86 (1H, m), 5.01(1H, d, J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2Hz), 5.74 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H,d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 719 (M+H)⁺.

Example 120(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 120)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H,s), 1.38-1.75 (17H, m), 1.78 (3H, d, J=0.88 Hz), 1.79-1.86 (2H, m), 1.86(1H, dd, J=5.2, 14.0 Hz), 2.45-2.64 (8H, m), 2.67 (1H, dd, J=2.4, 8.0Hz), 2.89 (1H, dt, J=2.4, 6.0 Hz), 3.32 (3H, s), 3.39-3.57 (5H, m),3.78-3.85 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.56(1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d,J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 733 (M+H)⁺.

Example 121(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 121)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.20-1.29 (4H, m), 1.34 (3H,s), 1.40-1.69 (7H, m), 1.74-1.82 (4H, m), 1.83-1.93 (2H, m), 2.38 (1.2H,s), 2.41 (1.8H, s), 2.44-2.63 (3H, m), 2.65-2.71 (2H, m), 2.75-2.85 (1H,m), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.20-3.30 (1H, m), 3.33 (1.8H, s),3.34 (1.2H, s), 3.46-3.59 (3H, m), 3.79-3.85 (1H, m), 4.32 (0.4H, s),4.42 (0.6H, s), 4.98-5.04 (1H, m), 5.06 (1H, d, J=10.4 Hz), 5.56 (1H,dd, J=9.6, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z663 (M+H)⁺.

Example 122(8E,12E,14E)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 122)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.05-1.13 (3H, m), 1.20-1.30(4H, m), 1.34 (3H, s), 1.38-1.69 (7H, m), 1.78 (3H, d, J=0.8 Hz),1.83-1.91 (2H, m), 2.45-2.72 (8H, m), 2.82-2.93 (2H, m), 3.20-3.31 (1H,m), 3.33 (1.5H, s), 3.34 (1.5H, s), 3.50-3.64 (3H, m), 3.79-3.85 (1H,m), 4.32 (0.5H, s), 4.42 (0.5H, s), 4.98-5.04 (1H, m), 5.06 (1H, d,J=10.8 Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.74 (1H, dd, J=10.0, 15.2Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H,dd, J=10.8, 15.2 Hz); ESI-MS m/z 677 (M+H)⁺.

Example 123(8E,12E,14E)-3,16,21-Trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 123)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.05-1.11 (6H, m), 1.19-1.30(4H, m), 1.34 (3H, s), 1.37-1.69 (7H, m), 1.73-1.90 (5H, m), 2.45-2.65(6H, m), 2.67 (1H, dd, J=2.4, 8.0), 2.89 (1H, dt, J=2.0, 6.0 Hz),3.01-3.20 (1H, m), 3.18-3.29 (1H, m), 3.32-3.35 (3H, m), 3.52 (1H, td,J=4.4, 8.4 Hz), 3.54-3.65 (1H, m), 3.76-3.86 (2H, m), 4.30 (5H, s), 4.40(0.5H, s), 4.98-5.09 (2H, m), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.70-5.79(1H, m), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 124(8E,12E,14E)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 124)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H,s), 1.37-1.69 (7H, m), 1.78 (3H, d, J=0.8 Hz), 1.86 (1H, dd, J=5.2, 14.0Hz), 2.27 (6H, s), 2.43-2.48 (4H, m), 2.48-2.62 (7H, m), 2.67 (1H, dd,J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.32 (3H, s), 3.41-3.59(5H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=10.0, 15.2 Hz),5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8,15.2 Hz); ESI-MS m/z 708 (M+H)⁺.

Example 125(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 125)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H,s), 1.39-1.69 (9H, m), 1.78 (3H, d, J=1.2 Hz), 1.83-1.90 (3H, m),1.98-2.07 (2H, m), 2.24-2.33 (1H, m), 2.25 (3H, s), 2.45-2.62 (7H, m),2.67 (1H, dd, J=2.4, 8.0 Hz), 2.87-2.96 (3H, m), 3.32 (3H, s), 3.41-3.58(5H, m), 3.79-3.86 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8Hz), 5.56 (1H, dd, J=10.0, 15.2 Hz), 5.73 (1H, dd, J=10.0, 15.2 Hz),5.87 (1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 734 (M+H)⁺.

Example 126(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(pyridin-4-yl)piperazin-1-ylcarbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 126)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H,s), 1.38-1.69 (7H, m), 1.78 (3H, d, J=1.2 Hz), 1.86 (1H, dd, J=5.2, 14.0Hz), 2.45-2.63 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.34 (3H, s), 3.40-3.47 (4H, m), 3.52 (1H, td, J=4.4,8.4 Hz), 3.56-3.72 (4H, m), 3.80-3.87 (1H, m), 5.05 (1H, d, J=9.2 Hz),5.07 (1H, d, J=10.4 Hz), 5.58 (1H, dd, J=10.0, 15.2 Hz), 5.76 (1H, dd,J=10.0, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, dd, J=1.2, 11.2Hz), 6.53 (1H, dd, J=11.2, 15.2 Hz), 6.86 (2H, d, J=6.4 Hz), 8.02-8.04(2H, m); ESI-MS m/z 714 (M+H)⁺.

Example 127(8E,12E,14E)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 127)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 85 except for using ethyltrifluoromethanesulfonate in the first step.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.16 (3H, t, J=7.2 Hz), 1.22(3H, s), 1.22-1.60 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J=6.4, 14.0 Hz),1.78 (3H, s), 1.86 (1H, dd, J=5.6, 13.6 Hz), 2.30 (3H, s), 2.36-2.43(4H, m), 2.43-2.69 (4H, m), 2.89 (1H, dt, J=2.4, 5.6 Hz), 3.43-3.61 (7H,m), 3.77-3.84 (1H, m), 4.98 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz),5.55 (1H, dd, J=10.0, 15.2 Hz), 5.76 (1H, dd, J=9.6, 15.2 Hz), 5.86 (1H,d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 665 (M+H)⁺.

Example 128(8E,12E,14E)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 128)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 127.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.0 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.17 (3H, t, J=6.8 Hz), 1.22(3H, s), 1.22-1.69 (16H, m), 1.34 (3H, s), 1.78 (3H, s), 1.83-1.93 (3H,m), 2.42-2.63 (8H, m), 2.67 (1H, dd, J=2.4, 7.6 Hz), 2.70-2.92 (3H, m),3.49-3.62 (3H, m), 3.77-3.84 (1H, m), 4.13-4.27 (2H, m), 4.98 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.54 (1H, dd, J=10.0, 15.2 Hz), 5.76(1H, dd, J=9.6, 15.6 Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.0Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 733 (M+H)⁺.

Example 129(8E,12E,14E)-7-Acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,2,1-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 129)

A solution of(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(221 mg, 0.4 mmol), N,N-dimethylaminopyridine (25 mg, 0.2 mmol) andtriethylamine (613 mg, 6 mmol) in dichloromethane (7 mL) was cooled to5° C., a solution of chlorotriethylsilane (609 mg, 4 mmol) indichloromethane (3 mL) was added dropwise thereto, and the reactionmixture was stirred at room temperature for one hour. The reactionmixture was diluted with ethyl acetate, washed with water and asaturated aqueous solution of sodium bicarbonate, dried over anhydrousmagnesium sulfate and evaporated. The resulting residue was purified bysilica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm;ethyl acetate-hexane, 1:9 to 1:4 to 1:3) to give the title compound (320mg, quantitative) as a colorless oil.

ESI-MS m/z 803 (M+Na)⁺.

Example 130(8E,12E,14E)-3,6,16-Trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130)

First Step

(8E,12E,14E)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,21-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-1)

To a solution of Compound 129(8E,12E,14E)-7-acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(320 mg, 0.41 mmol) obtained in Example 129 and ethylvinyl ether (589mg, 8 mmol) in dichloromethane (6 mL) was added a solution of pyridiniump-toluenesulfonate (5 mg, 20 μmol) in dichloromethane (1 mL) at roomtemperature, and the reaction mixture was stirred at the sametemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water and a saturated aqueous solution of sodiumbicarbonate, dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 to 1:7) togive the title compound (252 mg, 67%) as a colorless oil.

ESI-MS m/z 947 (M+Na)⁺.

Second Step

(8E,12E,14E)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-3,2,1-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-2)

A solution of Compound 130-1(8E,12E,14E)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,2,1-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(107 mg, 0.1156 mmol) obtained in the first step in tetrahydrofuran (6mL) was cooled to 5° C., tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 0.25 mL, 0.25 mmol) was added dropwisethereto, and the reaction mixture was stirred at room temperature for1.5 hours. The reaction mixture was diluted with ethyl acetate and thenwashed with water and a saturated aqueous solution of sodiumbicarbonate, dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:1 to 2:1) togive the title compound (81 mg, 100%) as a colorless oil.

ESI-MS m/z 719 (M+Na)⁺.

Third Step

(8E,12E,14E)-7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-3)

A solution of Compound 130-2(8E,12E,14E)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-3,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(33.2 mg, 47.6 μmol) obtained in the second step,N,N-dimethylaminopyridine (3 mg, 23.8 μmol) and triethylamine (49 mg,0.476 mmol) in dichloromethane (1 mL) was cooled to −20° C.,diethylisopropylsilyl chloride (10.3 mg, 59.5 μmol) was added dropwisethereto, and the reaction mixture was stirred at −20° C. to 5° C. for1.2 hours. Next, diethylisopropylsilyl chloride (31 mg, 179 μmol) wasadded dropwise to the reaction mixture at the same temperature, followedby stirring for 4.5 hours. Further, diethylisopropylsilyl chloride (41.2mg, 238 μmol) was added dropwise to the reaction mixture at the sametemperature, followed by stirring for 1.3 hours, and then stirring atroom temperature for one hour. The reaction mixture was diluted withethyl acetate, washed with water and a saturated aqueous solution ofsodium bicarbonate, dried over anhydrous magnesium sulfate andevaporated. The resulting residue was purified by thin layerchromatography (Merck Art 1.05628; ethyl acetate-hexane, 1:2) to givethe title compound (19.1 mg, 49%) as a colorless oil.

ESI-MS m/z 847 (M+Na)⁺.

Fourth Step

(8E,12E,14E)-7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-4)

A solution of Compound 130-3(8E,12E,14E)-7-acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(33.2 mg, 40 μmol) obtained in the third step and1,8-bis(N,N-dimethylamino)naphthalene (51.4 mg, 0.24 mmol) in toluene(0.7 mL) was cooled to 5° C., and methyl trifluoromethanesulfonate (20mg, 0.12 mmol) was added dropwise to the reaction mixture, followed byaddition of 0.5 mL of toluene. The reaction mixture was stirred at 50°C. for 12.5 hours. The reaction mixture was cooled to room temperature,diluted with toluene, and 0.06 N aqueous ammonia (5 mL) was added at 5°C., followed by stirring at room temperature for about 20 minutes. Ethylacetate, water and a saturated aqueous solution of ammonium chloridewere added thereto, the mixture was stirred for a while, and the organiclayer was separated. The organic layer was washed with a 0.05 M aqueoussolution of citric acid and an aqueous solution of sodium bicarbonatesuccessively, dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 to 1:7 to1:4 to 1:3) to give the title compound (15.8 mg, 47%) as a colorlessoil.

ESI-MS m/z 861 (M+Na)⁺.

<Fifth Step>

(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-5)

To Compound 130-4(8E,12E,14E)-7-acetoxy-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(21.5 mg, 25.6 μmol) obtained in the fourth step was added a 0.2Msolution of guanidine/guanidine nitrate (methanol-dichloromethane, 9:1)(0.26 mL, 52 μmol), followed by stirring at room temperature for 12.5hours. The reaction mixture was diluted with ethyl acetate, washed withwater and a saturated aqueous solution of ammonium chloride, dried overanhydrous magnesium sulfate and evaporated. The resulting residue waspurified by silica gel column chromatography (Kanto silica gel 60N, 40to 50 μm; ethyl acetate-hexane, 1:7 to 1:5 to 1:4) to give the titlecompound (19.3 mg, 95%) as a colorless oil.

ESI-MS m/z 819 (M+Na)⁺.

Sixth Step

(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-6)

A solution of Compound 130-5(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(19.3 mg, 24.2 μmol) obtained in the fifth step,N,N-dimethylaminopyridine (3 mg, 24.2 μmol) and triethylamine (25 mg,0.242 mmol) in dichloromethane (1.2 mL) was cooled to 5° C., a solutionof 4-nitrophenyl chloroformate (25 mg, 121 μmol) in dichloromethane (0.3mL) was added dropwise thereto, followed by stirring at room temperaturefor three hours. The reaction mixture was diluted with ethyl acetate andthen washed with an aqueous solution of sodium bicarbonate. Further theorganic layer was sequentially washed with an aqueous solution ofammonium chloride, an aqueous solution of sodium bicarbonate and waterin this order. The organic layer was dried over anhydrous magnesiumsulfate and evaporated to give a residue of the title compound (40.7 mg)as a pale yellow solid.

This solid was subjected to the subsequent reaction withoutpurification.

Seventh Step

(8E,12E,14E)-3-Diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-7)

A solution of the crude product of Compound 130-6(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-21-methoxy-7-(4-nitrophenoxy)carboxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(20.4 mg, 12.1 μmol) obtained in the sixth step in tetrahydrofuran (0.9mL) was cooled to 5° C., and a solution of 1-isopropylpiperazine (2.4mg, 18.2 μmol) in tetrahydrofuran (0.1 mL) and triethylamine (3.7 mg,36.3 μmol) were added dropwise thereto, followed by stirring at roomtemperature for 6.5 hours. The reaction mixture was diluted with ethylacetate, washed with water and a saturated aqueous solution of sodiumbicarbonate, dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by thin layer chromatography (FujiSilysia NH Silica gel plate; ethyl acetate-hexane, 1:3) to give thetitle compound (10.0 mg, 87%, two steps) as a colorless oil.

ESI-MS m/z 951 (M+H)⁺.

Eighth Step

(8E,12E,14E)-6,16-Bis(1-ethoxyethoxy)-3-hydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130-8)

A solution of Compound 130-7(8E,12E,14E)-3-diethylisopropylsiloxy-6,16-bis(1-ethoxyethoxy)-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(10 mg, 10.5 μmol) obtained in the seventh step in tetrahydrofuran (1.0mL) was cooled to 5° C., and tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 11.6 μl, 11.6 μmol) was added dropwisethereto, followed by stirring at room temperature for 1.5 hours. Thereaction mixture was diluted with ethyl acetate, washed with water and asaturated aqueous solution of sodium bicarbonate, dried over anhydrousmagnesium sulfate and evaporated. The resulting residue was purified bythin layer chromatography (Merck Art 1.05628; methanol-dichloromethane,1:29) to give the title compound (7.4 mg, 86%) as a colorless oil.

ESI-MS m/z 823 (M+11)⁺.

Ninth Step

(8E,12E,14E)-3,6,16-Trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 130)

To a solution of Compound 130-8(8E,12E,14E)-6,16-bis(1-ethoxyethoxy)-3-hydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(7.4 mg, 9 μmol) obtained in the eighth step in a mixture oftetrahydrofuran:2-methyl-2-propanol=1:1 (0.7 mL) was added pyridiniump-toluenesulfonate (6.8 mg, 27 μmol), followed by stirring at roomtemperature for 24 hours. The reaction mixture was diluted with ethylacetate, washed with water and a saturated aqueous solution of sodiumbicarbonate, dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by thin layer chromatography (FujiSilysia NH Silica gel plate; methanol-dichloromethane, 1:39) to give thetitle compound (4.2 mg, 69%) as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.2 Hz), 0.88(3H, t, J=7.6 Hz), 0.89 (3H, d, J=6.8 Hz), 1.07 (6H, d, J=6.4 Hz), 1.21(3H, s), 1.28-1.70 (11H, m), 1.77 (3H, d, J=1.2 Hz), 1.85 (1H, dd,J=5.2, 14.0 Hz), 2.47-2.62 (7H, m), 2.64 (1H, dd, J=2.4, 8.1 Hz),2.67-2.74 (1H, m), 2.88 (1H, dt, J=2.4, 6.0 Hz), 3.14-3.19 (1H, m), 3.38(3H, s), 3.42-3.70 (4H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J=10.0 Hz),5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72 (1H, dd,J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=10.8 Hz), 6.53(1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 679 (M+H)⁺.

Example 131(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 131)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 130.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.2 Hz), 0.88(3H, t, J=7.6 Hz), 0.89 (3H, d, J=6.8 Hz), 1.21 (3H, s), 1.29-1.70 (11H,m), 1.77 (3H, d, J=1.2 Hz), 1.85 (1H, dd, J=5.2, 14.0 Hz), 2.30 (3H, s),2.35-2.63 (7H, m), 2.64 (1H, dd, J=2.4, 8.0 Hz), 2.88 (1H, dt, J=2.4,6.0 Hz), 3.14-3.20 (1H, m), 3.38 (3H, s), 3.39-3.71 (4H, m), 3.75-3.82(1H, m), 4.93 (1H, d, J=10.0 Hz), 5.06 (1H, d, J=10.8 Hz), 5.57 (1H, dd,J=9.6, 15.2 Hz), 5.72 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz),6.13 (1H, dd, J=1.2, 10.8 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MSm/z 651 (M+H)⁺.

Example 132(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 132)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 130.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.2 Hz), 0.88(3H, t, J=7.6 Hz), 0.89 (3H, d, J=6.8 Hz), 1.22 (1.2H, s), 1.23 (1.8H,s), 1.28-1.71 (11H, m), 1.77 (3H, d, J=0.8 Hz), 1.81-1.93 (3H, m), 2.34(1.2H, s), 2.35 (1.8H, s), 2.50-2.67 (8H, m), 2.88 (1H, dt, J=2.0, 6.0Hz), 3.14-3.20 (1H, m), 3.38 (3H, s), 3.47-3.56 (2H, m), 3.58-3.67 (2H,m), 3.75-3.82 (1H, m), 4.95 (11H, d, J=10.0 Hz), 5.07 (1H, d, J=10.8Hz), 5.57 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz); ESI-MS m/z 665 (M+H)⁺.

Example 133(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 133)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 130.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=7.2 Hz), 0.88(3H, t, J=7.6 Hz), 1.89 (3H, d, J=6.8 Hz), 1.08 (1.5H, t, J=7.2 Hz),1.09 (1.5H t, J=7.2 Hz), 1.22 (1.5H, s), 1.23 (1.5H, s), 1.28-1.70 (11H,m), 1.77 (3H, d, J=1.2 Hz), 1.82-1.91 (3H, m), 2.47-2.76 (10H, m), 2.88(1H, dt, J=2.4, 6.0 Hz), 3.14-3.19 (1H, m), 3.38 (3H, s), 3.45-3.67 (4H,m), 3.75-3.82 (1H, m), 4.95 (1H, d, J=9.6 Hz), 5.07 (1H, d, J=10.8 Hz),5.57 (1H, dd, J=9.6, 15.2 Hz), 5.73 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H,d, J=15.2 Hz), 6.13 (11H, d, J=11.2 Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 679 (M+H)⁺.

Example 134(8E,12E,14E)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 134)

First Step

(8E,12E,14E)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenoxy)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 134-1)

To a solution of Compound 46-1(8E,12E,14E)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(44 mg, 49 μmol) obtained in the first step of Example 46 indichloromethane (2.0 mL) were added triethylamine (30 mg, 0.29 mmol),N,N-dimethylaminopyridine (90 mg, 0.73 mmol) and 4-nitrophenylchloroformate (90 mg, 0.44 mmol) under ice-cooling, and the reactionmixture was stirred at room temperature under nitrogen atmosphere forthree days. The reaction mixture was diluted with ethyl acetate andwashed with a saturated aqueous solution of sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtrated and evaporated. The resulting residue was purified by silicagel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethylacetate:hexane=10:90) to give the title compound (19 mg, 36%) as acolorless oil.

ESI-MS m/z 1082 (M+Na)⁺.

Second Step

(8E,12E,14E)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 134-2)

To a solution of Compound 134-1(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenyl)carboxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-1-olide(9 mg, 8.5 μmol) obtained in the first step in tetrahydrofuran (1 mL)were added triethylamine (8 mg, 85 μmol) and 1-methylpiperazine (1.7 mg,17 μmol) at room temperature, followed by stirring at the sametemperature under nitrogen atmosphere for 4 hours. The reaction mixturewas diluted with ethyl acetate and then washed with brine. The organiclayer was dried over anhydrous sodium sulfate, filtrated and evaporated.The resulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=50:50) to givethe title compound (8.6 mg, 100%) as a colorless oil.

ESI-MS m/z 1021 (M+H)⁺.

Third Step

(8E,12E,14E)-7-Acetoxy-3,6,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 134)

To a solution of Compound 134-2(8E,12E,14E)-7-acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide(9 mg, 8.51 mmol) obtained in the second step in tetrahydrofuran (1 mL)was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution,48 μL, 48 μmol) at room temperature, and the reaction mixture wasstirred at the same temperature under nitrogen atmosphere for 5 hours.The reaction mixture was diluted with ethyl acetate and washed withbrine. The organic layer was dried over anhydrous sodium sulfate,filtrated and evaporated. The resulting residue was purified by silicagel column chromatography (Kanto silica gel 60N, 40 to 100 μm;methanol:dichloromethane=5:95) to give the title compound (4.4 mg, 77%)as a colorless oil.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (6H, d, J=6.8 Hz), 0.94(3H, t, J=7.2 Hz), 1.20-1.28 (1H, m), 1.34 (3H, s), 1.38-1.70 (10H, in),1.78 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.04 (3H, s), 2.31 (3H, s),2.38-2.48 (4H, m), 2.48-2.52 (2H, m), 2.56-2.65 (1H, m), 2.66 (1H, dd,J=2.0, 7.6 Hz), 2.89 (1H, dt, J=2.0, 6.4 Hz), 3.42-3.62 (5H, m),3.76-3.84 (1H, m), 5.01 (1H, d, J=9.6 Hz), 5.06 (1H, d, J=10.8 Hz), 5.63(1H, dd, J=9.6, 15.2 Hz), 5.75 (1H, dd, J=9.2, 15.2 Hz), 5.87 (1H, d,J=15.2 Hz), 6.14 (1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 679 (M+H)⁺.

Example 135(8E,12E,14E)7-Acetoxy-6-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 135)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 134.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.22-1.32 (1H, m), 1.34 (3H,m), 1.40-1.78 (20H, m), 1.79 (3H, s), 1.82-1.93 (3H, m), 2.05 (3H, s),2.39-2.47 (1H, m), 2.50 (2H, d, J=3.6 Hz), 2.54-2.66 (6H, m), 2.89 (1H,dt, J=2.0, 6.4 Hz), 3.37-3.64 (5H, m), 3.76-3.83 (1H, m), 5.07 (1H, d,J=10.8 Hz), 5.15 (1H, d, J=9.2 Hz), 5.63 (1H, dd, J=9.2, 15.2 Hz), 5.7(1H, dd, J=9.2, 15.2 Hz), 5.87 (1H, d, J=15.2 Hz), 6.14 (1H, d, J=10.8Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 761 (M+H)⁺.

Example 136(8E,12E,14E)-7-Acetoxy-6-((4-ethylhomopiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 136)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 134.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.89 (6H, d, J=7.2 Hz), 0.94(3H, t, J=7.2 Hz), 1.08 (3H, t, J=7.2 Hz), 1.20-1.28 (1H, m), 1.34 (3H,s), 1.38-1.70 (10H, m), 1.78 (3H, s), 1.83-1.91 (3H, m), 2.03 (3H, s),2.33-2.42 (1H, m), 2.50 (2H, d, J=3.9 Hz), 2.58-2.80 (7H, m), 2.89 (1H,dt, J=2.4, 6.4 Hz), 3.45-3.65 (5H, m), 3.75-3.84 (1H, m), 5.02 (1H, d,J=−9.6 Hz), 5.07 (1H, d, J=10.4 Hz), 5.63 (1H, dd, J=9.6, 15.2 Hz), 5.76(1H, dd, J=9.6, 15.6 Hz), 5.87 (1H, d, J=15.6 Hz), 6.14 (1H, d, J=11.2Hz), 6.53 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z 707 (M+H)⁺.

Example 137(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-N-isopropylthiocarbamoyloxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 137)

First Step

(8E,12E,14E)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-(N-isopropylthiocarbamoyloxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 137-1)

To a suspension of sodium hydride (60% oil dispersion, 2 mg, 0.052 mmol)in tetrahydrofuran (0.5 mL) was added dropwise a solution of(8E,12E,14E)-3,6,16,21-tetra(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-1-olide(19 mg, 0.019 mmol) obtained in Example 3-(2) in tetrahydrofuran (0.5mL) under ice-cooling and stirring, and the reaction mixture was stirredat room temperature for 10 minutes. Then, isopropyl isothiocyanate (6.6mg, 0.066 mmol) was added dropwise thereto, and the reaction mixture wasstirred at room temperature for three hours. Water was added to thereaction mixture under ice-cooling to terminate the reaction, followedby diluting with ethyl acetate and washing with brine. The organic layerwas dried over anhydrous sodium sulfate and evaporated. The resultingresidue was purified by silica gel column chromatography (Kanto silicagel 60N, 40 to 100 μm; ethyl acetate:hexane=25:75) to give the titlecompound (10 mg, 60%) as a colorless oil.

ESI-MS m/z 922 (M+Na)⁺.

Second Step

(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-(N-isopropylthiocarbamoyloxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 137)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 3-5.

¹H-NMR Spectrum (CD₃ OD, 400 MHz) δ(ppm): 0.89 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.14-1.69 (20H, m), 1.77 (3H,s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.48-2.60 (3H, m), 2.66 (1H, dd,J=2.0, 8.0 Hz), 2.89 (1H, dt, J=2.0, 6.0 Hz), 3.49-4.08 (1H, m),3.73-3.83 (1H, m), 4.23-4.34 (1H, m) 4.95 (1H, d, J=9.6 Hz), 5.07 (1H,d, J=10.4 Hz), 5.60-5.92 (3H, m), 6.13 (1H, d, J=10.8 Hz), 6.52 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 634 (M+Na)⁺.

Example 138(8E,12E,14E)-7-(N-Butylthiocarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 138)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 137.

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.937 (3H, t, J=7.2 Hz), 0.942 (3H, t, J=7.2 Hz),1.19 (3H, s), 1.19-1.69 (15H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.6,14.0 Hz), 2.49-2.62 (3H, m), 2.66 (1H, dd, J=2.0, 8.0 Hz), 2.89 (1H, dt,J=2.0, 6.0 Hz), 3.42-3.57 (3H, m), 3.73-3.83 (1H, m), 4.95 (1H, d, J=9.6Hz), 5.07 (1H, d, J=10.4 Hz), 5.62-5.92 (3H, m), 6.14 (1H, d, J=10.8Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 648 (M+Na)⁺.

Example 139(8E,12E,14E)-7-(N-(3-(N′,N′-Diethylamino)propyl)thiocarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 139)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 137.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.4 Hz), 0.90(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.14 (6H, t, J=6.8 Hz), 1.19(3H, s), 1.21-1.69 (13H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0Hz), 2.48-2.61 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz), 3.70-3.86 (6H, m),2.89 (1H, dt, J=2.4, 5.6 Hz), 3.44-3.58 (3H, m), 3.75-3.83 (1H, m), 4.96(1H, d, J=8.4 Hz), 5.07 (H1H, d, J=10.4 Hz), 5.64-5.92 (3H, m), 6.14(1H, d, J=10.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 683(M+H)⁺.

Example 140(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 140)

First Step

(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 140-1)

To a solution of(8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(10 mg, 12.5 μmol) obtained in Example 3-2 in pyridine (0.5 mL) wereadded N,N-dimethylaminopyridine (8 mg, 62.5 μmol) and benzyl chloride(17.6 mg, 125 μmol) at room temperature, and the reaction mixture wasstirred at the same temperature under nitrogen atmosphere for 12 hours.The reaction mixture was diluted with ethyl acetate and washed with asaturated aqueous solution of ammonium chloride and brine. The organiclayer was dried over anhydrous magnesium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=25:75) to givethe title compound (6 mg, 55%) as a colorless oil.

ESI-MS m/z 925 (M+Na)⁺.

Second Step

(8E,12E,14E)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 140)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 3-5.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.93 (3H, t, J=7.2 Hz), 1.20-1.76 (14H, m), 1.78 (3H,s), 1.86 (1H, dd, J=5.6, 14.0 Hz), 2.53-2.64 (3H, m), 2.66 (1H, dd,J=2.4, 8.0 Hz), 2.89 (1H, dt, J=2.4, 5.6 Hz), 3.52 (1H, dt, J=4.8, 8.0Hz), 3.78-3.85 (1H, m), 5.09 (1H, d, J=10.81 Hz), 5.29 (1H, d, J=9.6Hz), 5.69 (1H, dd, J=9.6, 15.2 Hz), 5.83 (1H, dd, J=9.6, 15.2 Hz), 5.87(1H, d, J=15.2 Hz), 6.14 (1H, d, J=10.4 Hz), 6.53 (1H, dd, J=10.8, 15.2Hz), 7.47 (2H, dd, J=7.6, 7.6 Hz), 7.60 (1H, dd, J=7.6, 7.6 Hz), 8.12(2H, d, J=7.6 Hz); ESI-MS m/z 637 (M+Na)⁺.

Example 141(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-propanoyloxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 141)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 140.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 0.89(3H, d, J=7.2 Hz), 0.94 (3H, t, J=7.2 Hz), 1.11 (3H, t, J=8.0 Hz), 1.18(3H, s), 1.22-1.68 (11H, m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0Hz), 2.28-2.45 (2H, m), 2.50-2.61 (3H, m), 2.66 (1H, dd, J=2.4, 8.0 Hz),2.89 (1H, dt, J=2.0, 6.0 Hz), 3.52 (1H, dt, J=4.8, 8.0 Hz), 3.75-3.82(1H, m), 4.95 (1H, d, J=9.6 Hz), 5.05 (1H, d, J=9.6 Hz), 5.57 (1H, dd,J=10.0, 15.2 Hz), 5.70 (1H, dd, J=9.6, 15.2 Hz), 5.87 (1H, d, J=15.2Hz), 6.13 (1H, d, J=0.8 Hz), 6.52 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z589 (M+Na)⁺.

Example 142(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(3-phenylpropanoyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 142)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 140.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.86 (3H, d, J=6.8 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.2 Hz), 1.09 (3H, s), 1.20-1.69 (11H,m), 1.77 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.46-2.59 (3H, m),2.62-2.70 (3H, m), 2.85-2.96 (3H, m), 3.48-3.56 (1H, in), 3.72-3.80 (1H,m), 5.03 (1H, d, J=9.2 Hz), 5.05 (1H, d, J=10.8 Hz), 5.54 (1H, dd,J=9.6, 15.2 Hz), 5.66 (1H, dd, J=9.2, 15.2 Hz), 5.87 (1H, d, J=14.8 Hz),6.13 (1H, d, J=10.8 Hz), 6.53 (1H, dd, J=10.8, 14.8 Hz), 7.12-7.28 (5H,m); ESI-MS m/z 665 (M+Na)⁺.

Example 143(8E,12E,14E)-7-(Hexanoyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 143)

The title compound (a colorless oil) was obtained by a similar method asdescribed for Example 140.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.76-0.83 (9H, m), 0.98 (3H, t,J=7.2 Hz), 1.23 (3H, s), 1.24-1.74 (17H, m), 1.82 (3H, brs), 1.91 (1H,dd, J=5.6, 14.4 Hz), 2.32-2.44 (2H, m), 2.52-2.69 (3H, m), 2.71 (1H, dd,J=2.4, 8.0 Hz), 2.94 (1H, dt, J=2.4, 6.0 Hz), 3.53-3.60 (1H, m),3.78-3.86 (1H, m), 5.10 (1H, d, J=9.6 Hz), 5.11 (1H, d, J=9.6 Hz), 5.61(1H, dd, J=9.6, 15.2 Hz), 5.74 (1H, dd, J=9.6, 15.2 Hz), 5.91 (1H, d,J=15.2 Hz), 6.18 (1H, d, J=11.2 Hz), 6.57 (1H, dd, J=11.2, 15.2 Hz);ESI-MS m/z 631 (M+Na)⁺.

Example 144(8E,12E,14E)-7,21-Diacetoxy-3,6,16-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 144-1) and(8E,12E,14E)-3,7,21-triacetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 144-2)

Compound 144-1

Compound 144-2

A solution of(8E,12E,14E)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(276 mg, 0.5 mmol), N,N-dimethylaminopyridine (31 mg, 0.25 mmol) andtriethylamine (256 mg, 2.5 mmol) in dichloromethane (15 mL) was cooledto −20° C., a solution of acetic anhydride (53 mg, 0.5 mmol) indichloromethane (2 mL) was added dropwise thereto over 30 minutes, andthe reaction mixture was stirred at the same temperature for 30 minutes.A solution of acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1mL) was added dropwise to the reaction mixture over 30 minutes, followedby stirring at the same temperature for 2.5 hours. Further, a solutionof acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1 mL) wasadded dropwise to the reaction mixture over 5 minutes, followed bystirring at the same temperature for 30 minutes. Furthermore, a solutionof acetic anhydride (21 mg, 0.2 mmol) in dichloromethane (1 mL) wasadded dropwise to the reaction mixture over 5 minutes, followed bystirring at the same temperature for 30 minutes. The reaction mixturewas diluted with ethyl acetate, washed with water and a saturatedaqueous solution of sodium bicarbonate, dried over anhydrous magnesiumsulfate and evaporated. The resulting residue was purified by silica gelcolumn chromatography (Kanto silica gel 60N, 40 to 50 μm; ethylacetate-hexane, 2:1 to 3:1 to 4:1 to 9:1) to give the residue ofCompound 144-1 as a colorless oil, and Compound 144-2 (67.7 mg, 21%) ascolorless crystals. The residue of Compound 144-1 was then purified bythin layer chromatography (Merck Art 1.13792; ethyl acetate-hexane, 8:1to 9:1) to give Compound 144-1 (214.3 mg, 72%) as a colorless oil.

Compound 144-1

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.87 (3H, t, J=7.6 Hz), 0.88(3H, d, J=7.2 Hz), 0.92 (3H, d, J=6.8 Hz), 1.18 (3H, s), 1.31-1.68 (11H,m), 1.77 (3H, d, J=0.8 Hz), 1.82 (1H, dd, J=5.2, 14.0 Hz), 2.05 (3H, s),2.06 (3H, s), 2.46-2.63 (4H, m), 2.88 (1H, dt, J=2.0, 6.0 Hz), 3.75-3.81(1H, m), 4.84-4.92 (1H, covered with H₂O), 5.04 (1H, d, J=9.6 Hz), 5.05(1H, d, J=10.8 Hz), 5.56 (1H, dd, J=9.6, 15.2 Hz), 5.70 (1H, dd, J=9.6,15.2 Hz), 5.86 (1H, d, J=15.2 Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H,dd, J=10.8, 15.2 Hz); ESI-MS m/z 617 (M+Na)⁺.

Compound 144-2

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.87 (3H, t, J=7.6 Hz), 0.89(3H, d, J=6.8 Hz), 0.91 (3H, d, J=6.8 Hz), 1.18 (3H, s), 1.33 (3H, s),1.34-1.73 (8H, m), 1.77 (3H, d, J=0.8 Hz), 1.83 (1H, dd, J=5.6, 14.0Hz), 2.04 (3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.53-2.68 (4H, m), 2.88(1H, dt, J=2.0, 6.0 Hz), 4.78-4.96 (2H, covered with H₂O), 4.99 (1H, d,J=10.4 Hz), 5.02 (11H, d, J=9.6 Hz), 5.57 (11H, dd, J=9.6, 15.2 Hz),5.72 (1H, dd, J=9.6, 15.2 Hz), 5.86 (1H, d, J=15.2 Hz), 6.14 (1H, dd,J=1.2, 10.8 Hz), 6.52 (1H, dd, J=11.2, 15.2 Hz); ESI-MS m/z 659 (M+Na)⁺.

Example 145(8E,12E,14E)-21-Acetoxy-3,6,16-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 145-1) and(8E,12E,14E)-3,21-diacetoxy-6,16-dihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 145-2)

Compound 145-1

Compound 145-2

The title compounds (each a colorless oil) were synthesized by a similarmethod as described for Example 144 except for using Compound 44obtained in Example 44.

Compound 145-1

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.91 (3H, t, J=7.2 Hz), 0.93(3H, d, J=6.8 Hz), 0.96 (3H, d, J=7.2 Hz), 1.12 (6H, d, J=6.4 Hz), 1.26(3H, s), 1.30-1.56 (6H, m), 1.58-1.76 (5H, m), 1.82 (3H, s), 1.87 (1H,dd, J=5.6, 14.0 Hz), 2.10 (3H, s), 2.48-2.70 (8H, m), 2.70-2.82 (1H, m)2.93 (1H, dt, J=2.0, 5.6 Hz), 3.44-3.76 (4H, m), 3.78-3.88 (1H, m),4.86-4.98 (1H, covered with H₂O), 4.97 (1H, d, J=9.6 Hz), 5.10 (1H, d,J=10.8 Hz), 5.62 (1H, dd, J=10.0, 15.2 Hz), 5.76 (1H, dd, J=9.6, 15.2Hz), 5.90 (1H, d, J=15.2 Hz), 6.18 (1H, d, J=10.8 Hz), 6.57 (1H, dd,J=10.8, 15.2 Hz); ESI-MS m/z 707 (M+H)⁺.

Compound 145-2

¹H-NMR Spectrum (CD₃OD, 40 MHz) δ(ppm): 0.91 (3H, t, J=7.6 Hz), 0.93(3H, d, J=6.8 Hz), 0.96 (3H, d, J=7.2 Hz), 1.12 (6H, d, J=6.4 Hz), 1.25(3H, s), 1.30-1.92 (15H, m), 2.088 (3H, s), 2.094 (3H, s), 2.50-2.80(9H, m), 2.93 (1H, dt, J=2.0, 6.0 Hz), 3.40-3.76 (4H, m), 4.80-4.96 (2H,covered with H₂O), 4.96 (1H, d, J=9.6 Hz), 5.04 (1H, d, J=10.8 Hz), 5.63(1H, dd, J=10.0, 15.2 Hz), 5.78 (1H, dd, J=9.6, 15.2 Hz), 5.91 (1H, d,J=15.2 Hz), 6.18 (1H, d, J=10.8 Hz), 6.56 (1H, dd, J=10.8, 15.2 Hz);ESI-MS m/z 749 M⁺.

Example 146(8E,12E,14E)-6,16-Dihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,2,1-dioxo-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 146-1) and(8E,12E,14E)-3,6,16-trihydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-21-oxo-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 146-2)

Compound 146-1

Compound 146-2

To a solution of Compound 44 (20 mg, 30 μmol) obtained in Example 44 indichloromethane (2.0 mL) was added Dess-Martin reagent (43 mg, 0.101mmol) under ice-cooling and stirring, and the reaction mixture wasstirred at room temperature under nitrogen atmosphere for six hours. Thereaction mixture was diluted with ethyl acetate and then washed with asaturated aqueous solution of sodium bicarbonate and brine. The organiclayer was dried over anhydrous sodium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography(Kanto silica gel 60N, 40 to 100 μm; dichloromethane:methanol=95:5 to90:10) to give the title compounds, Compound 146-1 (9.6 mg, 48%) andCompound 146-2 (8.9 mg, 45%), each as a colorless oil.

Compound 146-1

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.91 (3H, d, J=6.8 Hz), 1.00(3H, t, J=7.2 Hz), 1.07 (3H, d, J=7.2 Hz), 1.10 (6H, d, J=6.4 Hz), 1.30(3H, s), 1.33 (3H, s), 1.63 (1H, dd, J=6.8, 14.4 Hz), 1.74-1.80 (1H, m),1.80 (3H, s), 1.89 (1H, dd, J=5.6, 14.4 Hz), 2.00-2.08 (1H, m),2.28-2.37 (1H, m), 2.46 (2H, d, J=12.4 Hz), 2.52-2.70 (7H, m), 2.72-2.84(3H, m), 2.92 (1H, dt, J=2.0, 6.4 Hz), 3.31-3.33 (1H, m), 3.42-3.64 (4H,m), 4.94 (1H, d, J=8.0 Hz), 4.96 (1H, d, J=10.8 Hz), 5.23 (1H, dd,J=8.8, 15.6 Hz), 5.50 (1H, dd, J38.4, 15.6 Hz), 5.86 (1H, d, J=15.2 Hz),6.10 (1H, d, J=10.8 Hz), 6.54 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 661(M+H)⁺, 683 (M+Na)⁺.

Compound 146-2

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.88 (3H, d, J=6.8 Hz), 1.00(3H, t, J=7.2 Hz), 1.07 (3H, d, J=6.8 Hz), 1.10 (6H, d, J=7.2 Hz), 1.21(3H, s), 1.38-1.42 (5H, m), 1.54-1.68 (3H, m) 1.77 (3H, s), 1.89 (1H,dd, J=4.8, 14.0 Hz), 2.28-2.36 (1H, m), 2.50-2.64 (8H, m), 2.75 (1H, dd,J=2.0, 8.4 Hz), 2.76-2.84 (1H, m), 2.91 (1H, dt, J=2.4, 7.6 Hz),3.31-3.33 (1H, m), 3.42-3.64 (4H, m), 3.75-3.82 (1H, m), 4.93 (1H, d,J=9.6 Hz), 5.06 (1H, d, J=10.4 Hz), 5.57 (1H, dd, J=10.0, 15.2 Hz), 5.72(1H, dd, J=10.0, 15.2 Hz), 5.86 (1H, d, J=15.2 Hz)>6.14 (1H, d, J=10.8Hz), 6.53 (1H, dd, J=10.8, 15.2 Hz); ESI-MS m/z 663 (M+H)⁺, 685 (M+Na)⁺.

Example 147(8E,12E,14E)-7-Acetoxy-6-ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(Compound 147)

The title compound (a colorless oil) was synthesized by a similar methodas described for Example 43 except for using ethyltrifluoromethanesulfonate.

¹H-NMR Spectrum (CD₃OD, 400 MHz) δ(ppm): 0.87 (3H, d, J=6.4 Hz), 0.90(3H, d, J=6.8 Hz), 0.94 (3H, t, J=7.6 Hz), 1.17 (3H, t, J=7.2 Hz), 1.20(3H, s), 1.22-1.60 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J=6.4, 14.0 Hz),1.78 (3H, s), 1.86 (1H, dd, J=5.2, 14.0 Hz), 2.04 (3H, s), 2.44-2.68(4H, m), 2.89 (1H, dt, J=2.4, 5.2 Hz), 3.49-3.66 (3H, m), 3.77-3.84 (1H,m), 5.06 (1H, d, J=10.4 Hz), 5.10 (1H, d, J=9.6 Hz), 5.55 (1H, dd,J=9.6, 15.6 Hz), 5.75 (1H, dd, J=10.0, 15.6 Hz), 5.86 (1H, d, J=15.2Hz), 6.13 (1H, d, J=11.2 Hz), 6.52 (1H, dd, J=11.2, 15.6 Hz); ESI-MS m/z603 (M+Na)⁺.

FORMULATION EXAMPLE

Formulation Examples of the compounds of the present invention will beillustrated below, but the formulation of the compounds of the presentinvention is not limited to these Formulation Examples.

Formulation Example 1

Compound of Example 44 45 (part) Heavy magnesium oxide 15 Lactose 75

were mixed homogeneously and formulated into a powdered medicine in theform of a powder or fine granules having a size of 350 μm or less. Thepowdered medicine was charged into capsules to give capsule form.

Formulation Example 2

Compound of Example 75 45 (part) Starch 15 Lactose 16 Crystallinecellulose 21 Poly(vinyl alcohol) 3 Distilled water 30

were mixed homogeneously, pulverized, granulated, dried and then sievedto give granules having a size of 1410 to 177 μm.

Formulation Example 3

Granules were produced by a similar method as described for FormulationExample 2, 4 parts of calcium stearate was added to 96 parts of thegranules, compressed and molded to give tablets having a diameter of 10mm.

Formulation Example 4

To 90 parts of granules obtained by the method of Formulation Example 2were added 10 parts of crystalline cellulose and 3 parts of calciumstearate, compressed and molded to give tables having a diameter of 8mm. Then, a mixed suspension of syrup, gelatin and precipitated calciumcarbonate was added thereto to give sugar-coated tablets.

Formulation Example 5

Compound of Example 45 0.6 (part) Nonionic surfactant 2.4 Isotonicsodium chloride solution 97

were heated, mixed and charged into an ampoule, the ampoule wassterilized to produce an injection.

REFERENTIAL EXAMPLES Referential Example 11-(Cyclopropylmethyl)piperazine

The compound was synthesized by the following three steps.

Referential Example 1-1 Benzyl4-(cyclopropylcarbonyl)piperazin-1-carboxylate

In 35 mL of N,N-dimethylformamide were dissolved benzyl1-piperazinecarboxylate (5.00 g, 22.7 mmol) and cyclopropanecarboxylicacid (2.54 g, 29.5 mmol), and1-ethyl-3-(3-(N,N-dimethylamino)propyl)-carbodiimide hydrochloride (6.53g, 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) andtriethylamine (3.60 g, 35.9 mmol) were added thereto at roomtemperature, followed by stirring at the same temperature for threehours. The reaction mixture was mixed with water, and extracted twicewith ethyl acetate. The organic layer was sequentially washed with watertwice, with a saturated aqueous solution of sodium bicarbonate once andwith brine once, and then dried over anhydrous sodium sulfate. Theorganic layer was passed through a silica gel column (Fuji Silysia, NHSilica gel) and evaporated to give the title compound (6.10 g, 93.1%) asa white amorphous.

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 0.75-0.83 (2H, m), 0.95-1.03(2H, m), 1.65-1.75 (1H, m), 3.40-3.80 (8H, m), 5.16 (2H, s), 7.30-7.40(5H, m).

Referential Example 1-2 1-(Cyclopropylcarbonyl)piperazine

In 100 mL of ethanol was dissolved benzyl4-(cyclopropylcarbonyl)piperazine-1-carboxylate (3.00 g, 10.4 mmol), and1.5 g of 10% palladium-carbon was added thereto, followed by stirring atroom temperature under hydrogen atmosphere overnight. Thepalladium-carbon was removed by filtration, and the filtrate wasevaporated to give the title compound (1.50 g, 97.3%) as a colorlessoil. ¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 0.73-0.80 (2H, m),0.96-1.03 (2H, m), 1.67-1.77 (1H, m), 2.82-2.97 (4H, m), 3.60-3.71 (4H,m).

Referential Example 1-3 1-(Cyclopropylmethyl)piperazine

Lithium aluminium hydride (770 mg, 20.3 mmol) was suspended intetrahydrofuran (150 mL), 1-(cyclopropylcarbonyl)piperazine (1.56 g,10.1 mmol) was gradually added thereto, and the reaction mixture washeated under reflux for 30 minutes. The reaction mixture was cooled toroom temperature, and 0.8 mL of water, 0.8 mL of a 15% aqueous solutionof sodium hydroxide and 2.3 mL of water were sequentially graduallyadded thereto. The precipitated insoluble matter was removed byfiltration through Celite, and the filtrate was evaporated to give thetitle compound (1.40 g) as a colorless oil. The product was used for thesynthesis of(8E,12E,14E)-7-((4-cyclopropylmethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide(the compound of Example 27) without further purification.

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 0.09-0.15 (2H, m), 0.48-0.56(2H, m), 0.82-0.93 (1H, m), 2.25 (2H, d, J=7.2 Hz) 2.48-2.65 (4H, m),2.90-2.99 (4H, m).

Referential Example 2 1-Isobutylpiperazine

Benzyl 1-piperazinecarboxylate (1.1 g, 5.00 mmol) and isobutylaldehyde(0.91 mL, 10.0 mmol) were dissolved in 30 mL of tetrahydrofuran, andacetic acid (0.57 mL, 10.0 mmol) and sodium triacetoxyborohydride (2.11g, 10.0 mmol) were added thereto, and the reaction mixture was stirredat room temperature for two hours. The reaction mixture was mixed with a1N aqueous solution of sodium hydroxide, extracted with ethyl acetatetwice, and the combined organic layers were washed with brine once. Themixture was dried over anhydrous sodium sulfate and evaporated. Theresulting residue was purified by silica gel column chromatography (FujiSilysia, NH Silica gel; ethyl acetate:hexane=50:50) to give benzyl4-isobutylpiperazin-1-carboxylate (1.05 g) as a colorless oil.

The resulting benzyl 4-isobutylpiperazin-1-carboxylate (1.05 g) wasdissolved in 35 mL of ethanol, 10% palladium-carbon (750 mg) was addedthereto, and the reaction mixture was stirred at room temperature underhydrogen atmosphere (1 atm) for 12 hours. The palladium-carbon wasremoved by filtration, and the filtrate was evaporated to give the titlecompound (610 mg) as a colorless oil.

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 0.90 (6H, d, J=6.8 Hz),1.71-1.86 (1H, m), 2.07 (2H, d, J=7.6 Hz), 2.33-2.43 (4H, m), 2.86-2.93(4H, m).

Referential Example 3 1-(Tetrahydropyran-4-yl)piperazine

The title compound was synthesized by a similar method as described forthe compound of Referential Example 2 (1-isobutylpiperazine).

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 1.50-1.64 (2H, m), 1.72-1.80(2H, m), 2.36-2.46 (1H, m), 2.54-2.64 (4H, m), 2.91-2.97 (4H, m), 3.37(2H, dt, J=2.0, 11.6 Hz), 4.03 (2H, dd, J=4.4, 11.6 Hz).

Referential Example 4 1-(Cyclopropylmethyl)homopiperazine

Benzyl 1-homopiperazinecarboxylate (1.95 g, 8.32 mmol) andcyclopropanecarboxyaldehyde (700 mg, 10.0 mmol) were dissolved in 40 mLof tetrahydrofuran. Acetic acid (600 mg, 10.0 mmol) and sodiumtriacetoxyborohydride (2.11 g, 10.0 mmol) were added thereto, and thereaction mixture was stirred at room temperature for two hours. Thereaction mixture was mixed with 1 N aqueous solution of sodiumhydroxide, extracted with ethyl acetate twice, and the combined organiclayers were washed with brine once. The mixture was dried over anhydroussodium sulfate and evaporated. The resulting residue was purified bysilica gel column chromatography (Fuji Silysia, NH Silica gel; ethylacetate:hexane=50:50) to give benzyl4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) as a colorlessoil.

The resulting benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate(2.5 g) was dissolved in 50 mL of ethanol, 10% palladium-carbon (500 mg)was added, and the reaction mixture was stirred at room temperatureunder hydrogen atmosphere (1 atm) for 12 hours. The palladium-carbon wasremoved by filtration, and the filtrate was evaporated to give the titlecompound (1.4 g) as a colorless oil.

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 0.08-0.15 (2H, m), 0.47-0.56(2H, m), 0.82-0.95 (1H, m), 1.80-1.89 (2H, m), 2.44 (2H, d, J=6.4 Hz)2.75-2.85 (4H, m), 2.94-3.03 (4H, m).

Referential Example 5 1-(2,2,2-Trifluoroethyl)piperazine

Benzyl 1-piperazinecarboxylate (2.0 g, 9.08 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.5 g, 10.8 mmol) and triethylamine (1.9 mL,13.8 mmol) were dissolved in 50 mL of tetrahydrofuran, and the reactionmixture was stirred at 60° C. for two hours. After cooling to roomtemperature, the reaction mixture was mixed with a saturated aqueoussolution of sodium bicarbonate and extracted with ethyl acetate twice.The combined organic layers were sequentially washed with water andbrine in this order. The mixture was dried over anhydrous sodium sulfateand evaporated. The resulting residue was purified by silica gel columnchromatography (Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50)to give 4-(2,2,2-trifluoroethyl)piperazin-1-carboxylic acid benzyl ester(3.1 g) as a colorless oil.

Resulting benzyl 4-(2,2,2-trifluoroethyl)piperazin-1-carboxylate (3.1 g)was dissolved in 50 mL of ethanol, and 10% palladium-carbon (900 mg) wasadded, followed by stirring at room temperature under hydrogenatmosphere (1 atm) overnight. The palladium-carbon was removed byfiltration, and the filtrate was evaporated to give the title compound(1.4 g) as a colorless oil.

¹H-NMR Spectrum (CDCl₃, 400 MHz) δ(ppm): 2.64-2.77 (4H, m), 2.90-3.01(6H, m).

Referential Example 6

One loopful of the slant culture [0.5% of soluble starch, 0.5% ofglucose, 0.1% of fish meat extract (manufactured by Wako Pure ChemicalIndustries, Ltd.), 0.1% of yeast extract (manufactured by Oriental YeastCo., Ltd.), 0.2% of NZ-case (manufactured by Humko Sheffield ChemicalCo.), 0.2% of sodium chloride, 0.1% of calcium carbonate, and 1.6% ofagar (manufactured by Wako Pure Chemical Industries, Ltd.)] ofStreptomyces sp. AB-1704 strain (FERM P-18999) isolated from the soilwas inoculated into a 65 mL test tube containing 7 mL of a seed medium[2.0% of soluble starch, 1.0% of glucose, 0.5% of polypeptone(manufactured by Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract(manufactured by Oriental Yeast Co., Ltd.), and 0.1% of calciumcarbonate], and it was cultured at 28° C. for three days in a shakingincubator to give a seed culture.

Further, 0.5 mL of the seed culture was inoculated into a 65 mL testtube containing 7 mL of a production medium [2.0% of soluble starch,1.0% of glucose, 0.5% of polypeptone (manufactured by NihonPharmaceutical Co., Ltd.), 0.5% of yeast extract (manufactured byOriental Yeast Co., Ltd.), and 0.1% of calcium carbonate], and it wascultured at 28° C. for three days in a shaking incubator.

Next, a 25 mg/mL solution of the substrate 11107B substance (thecompound of Example A4 of WO 02/060890) in ethanol was prepared, and 0.2mL of the solution was added to the culture. After addition, it wasshaken at 28° C. for 48 hours to carry out conversion reaction.

After the reaction, the reaction mixture was analyzed by HPLC under thefollowing analytic HPLC condition (a) to verify that 11107D substancewas formed in the reaction mixture.

Analytic HPLC Condition (a)

Column: CAPCELL PAK C18 SG120 φ4.6 mm×250 mm (manufactured by SHISEIDOCo.)

Temperature. 40° C.

Flow rate: 1 mL/min.

Detection: 240 nm

Eluent: acetonitrile/0.15% potassium dihydrogenphosphate (pH 3.5) (3:7to 5:5, V/V, 0 to 18 minutes, linear gradient), acetonitrile/0.15%potassium dihydrogenphosphate (pH 3.5) (5:5 to 85:15, v/v, 18 to 22minutes, linear gradient)

Retention time: 11107D substance 9.9 min., 11107B substance 19.4 min.

Referential Example 7

One loopful of the slant culture (yeast-malt agar medium) of A-1545strain (FERM P-18944) isolated from the soil was inoculated into a 250mL Erlenmeyer flask containing 20 mL of a seed medium [2.4% of solublestarch, 0.1% of glucose, 0.5% of soybean meal (ESUSAN-MEAT manufacturedby Ajinomoto Co., Ltd.), 0.3% of beef extract (manufactured by Difco),0.5% of yeast extract (manufactured by Difco), 0.5% of triptone-peptone(manufactured by Difco), and 0.4% of calcium carbonate], and it wascultured at 28° C. for three days in a shaking incubator to give a seedculture.

Further, 0.6 mL of the seed culture was inoculated into a 500 mLErlenmeyer flask containing 60 mL of a production medium [2% of solublestarch, 2% of glucose, 2% of soybean meal (ESUSAN-MEAT manufactured byAjinomoto Co., Ltd.), 0.5% of yeast extract (manufactured by OrientalYeast Co., Ltd.), 0.25% of sodium chloride, 0.32% of calcium carbonate,0.0005% of copper sulfate, 0.0005% of manganese chloride, 0.0005% ofzinc sulfate, pH 7.4 before sterilization], and it was cultured at 28°C. for four days in a shaking incubator. Each 2 mL of the resultingculture was dispensed into 15 mL test tubes. Next, a 20 mg/mL solutionof the substrate 11107B substance in dimethyl sulfoxide was prepared,and 0.05 mL of the solution was added. After the addition, it was shakenat 28° C. for 23 hours to carry out conversion. After the reaction, thereaction mixture was analyzed by HPLC under the following analytic HPLCcondition (b) to verify that the 11107D substance was formed in thereaction mixture.

Analytic HPLC Condition (b)

Column: CAPCELL PAK C18 SG120 φ4.6 mm×250 mm (manufactured by SHISEIDOCo.)

Temperature: 40° C.

Flow rate: 1 mL/min.

Detection. 240 nm

Eluent: acetonitrile/water (50:50, v/v) isocratic

Retention time: 11107B substance 7.2 min., 11107D substance 3.6 min.

Referential Example 8

One loopful of the slant culture [0.5% of soluble starch, 0.5% ofglucose, 0.1% of fish meat extract (manufactured by Wako Pure ChemicalIndustries, Ltd.), 0.1% of yeast extract (manufactured by Oriental YeastCo., Ltd.), 0.2% of NZ-case (manufactured by Humko Sheffield ChemicalCo.), 0.2% of sodium chloride, 0.1% of calcium carbonate, and 1.6% ofagar (manufactured by Wako Pure Chemical Industries, Ltd.)] ofStreptomyces sp. AB-1704 strain (FERM P-18999) isolated from the soilwas inoculated into a 500-mL Erlenmeyer flask containing 100 mL of aseed medium [2.0% of soluble starch, 1.0% of glucose, 0.5% ofpolypeptone (manufactured by Nihon Pharmaceutical Co., Ltd.), 0.5% ofyeast extract (manufactured by Oriental Yeast Co., Ltd.), and 0.1% ofcalcium carbonate], and it was cultured at 28° C. for three days in ashaking incubator to give a seed culture. Further, each 2 mL of the seedculture was inoculated into 500 mL Erlenmeyer flasks (150 flasks) eachcontaining 100 mL of a production medium [2.0% of soluble starch, 1.0%of glucose, 0.5% of polypeptone (manufactured by Nihon PharmaceuticalCo., Ltd.), 0.5% of yeast extract (manufactured by Oriental Yeast Co.,Ltd.), and 0.1% of calcium carbonate], and it was cultured at 28° C. fortwo days in a shaking incubator.

A 20 mg/mL solution of the substrate 11107B substance in ethanol wasprepared, and each 0.44 mL of the solution was added to the culture (100mL/500 mL Erlenmeyer flask, 150 flasks). After the addition, it wasshaken at 28° C. for 9 hours to carry out conversion. After thecompletion of reaction, the cultures were collected and separated intothe culture supernatant and the mycelium cake by centrifugation at 2700rpm for 10 minutes. The mycelium cake was extracted with 5 L of methanoland filtrated to give the methanol extract. This methanol extract wasevaporated to remove methanol, combined with the culture supernatant andextracted with 10 L of ethyl acetate. The resulting ethyl acetatesolution was evaporated to give 2090 mg of a crude active fraction. Thecrude active fraction was dissolved in 4 mL of a mixture oftetrahydrofuran-methanol (1:1, v/v) and 6 mL of a 50% aqueous solutionof acetonitrile, subjected to ODS column chromatography (manufactured byYMC Co., ODS-AM 120-S50 φ3.6 cm×43 cm) and eluted with a 40% aqueoussolution of acetonitrile. An eluted fraction from 336 mL to 408 mL wasconcentrated to dryness under reduced pressure to give 560 mg of aresidue. Further, the residue was dissolved in 10 mL of a 50% aqueoussolution of methanol, subjected to ODS column chromatography(manufactured by YMC Co., ODS-AM 120-S50 φ3.6 cm×40 cm) and eluted witha 50% aqueous solution of methanol. An eluted fraction from 1344 mL to1824 mL was concentrated to dryness under reduced pressure to give 252mg of 11107D substance.

Referential Example 9

One loopful of the slant culture (yeast-malt agar medium) of A-1544strain (FERM P-18943) was inoculated into a 250 mL Erlenmeyer flaskcontaining 25 mL of a seed medium [2% of soluble starch, 2% of glucose,2% of soybean meal (ESUSAN-MEAT manufactured by Ajinomoto Co., Ltd.),0.5% of yeast extract (manufactured by Difco), 0.25% of sodium chloride,and 0.32% of calcium carbonate, pH 7.4 before sterilization], and it wascultured at 28° C. for two days in a shaking incubator to give a seedculture. Each 0.75 mL of the culture was dispensed into 2 mL serum tubes(manufactured by Sumitomo Bakelite Co., Ltd.), and an equal amount of a40% aqueous solution of glycerol was added. After stirring, it wasfrozen at −70° C. to give a frozen seed culture. The frozen seed culturewas melted, 0.25 mL thereof was inoculated into a 250 mL Erlenmeyerflask containing 25 mL of a seed medium [2% of soluble starch, 2% ofglucose, 2% of soybean meal (ESUSAN-MEAT manufactured by Ajinomoto Co.,Ltd.), 0.5% of yeast extract (manufactured by Oriental Yeast Co., Ltd.),0.25% of sodium chloride, and 0.32% of calcium carbonate, pH 7.4 beforesterilization], and it was cultured at 28° C. for two days in a shakingincubator to give a seed culture. Further, the seed culture (0.5 mL) wasinoculated into a 500 mL Erlenmeyer flask containing 100 mL ofproduction medium [2% of soluble starch, 2% of glucose, 2% of soybeanmeal (ESUSAN-MEAT manufactured by Ajinomoto Co., Ltd.), 0.5% of yeastextract (manufactured by Oriental Yeast Co., Ltd.), 0.25% of sodiumchloride, and 0.32% of calcium carbonate, pH 7.4 before sterilization],and it was cultured at 28° C. for three days in a shaking incubator.

Each of the resulting cultures (100 mL/500 mL Erlenmeyer flask, 10flasks) was subjected to centrifugation at 3000 rpm for 10 minutes tocollect cells, and the cells were suspended into 100 mL of a 50 mMphosphate buffer solution (pH 6.0). Next, a 100 mg/mL solution of thesubstrate 11107B substance in dimethyl sulfoxide was prepared, and each0.5 mL of the solution was added. After the addition, it was shaken at28° C. for 24 hours to carry out conversion. After the completion of thereaction, the reaction mixtures were collected and separated into thesupernatant and mycelium cake by centrifugation at 5000 rpm for 20minutes. The supernatant was extracted with 1 L of ethyl acetate. Themycelium cake was extracted with 500 mL of methanol and then filtratedto give a methanol extract. The methanol extract was evaporated toremove methanol and extracted with 1 L of ethyl acetate. Each of theethyl acetate layers was washed with water, dried over anhydrous sodiumsulfate, and the combined layers were evaporated to give 937 mg of acrude active fraction. The crude active fraction was subjected to silicagel column chromatography (Kiesel gel 60, 50 g) and eluted with 1200 mLof a mixture of ethyl acetate and n-hexane (90:10; v/v) to give 234 mgof an active fraction. The resulting active fraction was subjected topreparative high performance liquid chromatography (HPLC) under thefollowing preparative HPLC condition (C), and the resulting eluate wasanalyzed by HPLC under the following analytic HPLC condition (c). Thesolvent was removed from the fraction containing the 11107D substancethus obtained, to give 80 mg of the 11107D substance.

Preparative HPLC Condition (C)

Column: CAPCELL PAK C18 UG120 φ30×250 mm (manufactured by SHISEIDO Co.)

Flow rate. 20 mL/min.

Detection: 240 nm

Eluent: acetonitrile/water (30:70, v/v) isocratic

Analytic HPLC Condition (c)

Column: CAPCELL PAK C18 SG120 φ4.6 mm×250 mm (manufactured by SHISEIDOCo.)

Temperature: 40° C.

Flow rate: 1 mL/min.

Detection: 240 nm

Fluent: acetonitrile/water (35:65, v/v) isocratic

Retention time: 11107D substance 7.8 min.

Referential Example 10

Each of cultures of A-1545 strain (FERM P-18944) (100 mL/500 mLErlenmeyer flask, 10 flasks) obtained by a similar method as describedfor Referential Example 9 was subjected to centrifugation at 3000 rpmfor 10 minutes to collect cells, and the cells were suspended into 100mL of a 50 mM phosphate buffer solution (pH 6.0). Next, a 100 mg/mLsolution of the substrate 11107B in dimethyl sulfoxide was prepared, andeach 1 mL of the solution was added. After the addition, it was shakenat 28° C. for 24 hours to carry out conversion. After the completion ofthe reaction, the reaction mixtures were collected and separated intothe supernatant and mycelium cake by centrifugation at 5000 rpm for 20minutes. The supernatant was extracted with 1 L of ethyl acetate. Themycelium cake was extracted with 500 mL of acetone, and then filtratedto give an acetone extract. The acetone extract was evaporated to removeacetone, and extracted with 1 L of ethyl acetate. Each of the ethylacetate layers was washed with water, dried and dehydrated overanhydrous sodium sulfate, and the combined layers were evaporated togive 945 mg of a crude active fraction. The crude active fraction wassubjected to silica gel column chromatography (Kiesel gel 60, 50 g),eluted with 100 mL of a mixture of ethyl acetate and n-hexane (50:50;v/v), 200 mL of a mixture of ethyl acetate and n-hexane (75:25; v/v),and 600 mL of a mixture of ethyl acetate and n-hexane (90:10; v/v), togive 463 mg of an active fraction. The obtained active fraction wassubjected to preparative high performance liquid chromatography (HPLC)under the preparative HPLC condition (C) described in Example 4, theresulting eluate was analyzed by HPLC under the analytic HPLC conditiondescribed in Example 4. The solvent was removed from the fractioncontaining 11107D substance thus obtained, to give 304 mg of 11107Dsubstance.

1. A compound represented by the formula (I):

(in the formula, R³, R⁶, R⁷ and R²¹ are the same as or different fromone another and each represents 1) a hydroxyl group or an oxo groupformed together with the carbon atom to which each of R³, R⁶, R⁷ and R²¹is bound, provided that R⁶ is limited to hydroxyl group, 2) anoptionally substituted C₁₋₂₂ alkoxy group, 3) an optionally substitutedunsaturated C₂₋₂₂ alkoxy group, 4) an optionally substituted C₇₋₂₂aralkyloxy group, 5) an optionally substituted 5 to 14-memberedheteroaralkyloxy group, 6) RCO—O— (wherein R represents a) a hydrogenatom, b) an optionally substituted C₁₋₂₂ alkyl group, c) an optionallysubstituted unsaturated C₂₋₂₂ alkyl group, d) an optionally substitutedC₆₋₁₄ aryl group, e) an optionally substituted 5 to 14-memberedheteroaryl group, f) an optionally substituted C₇₋₂₂ aralkyl group, g)an optionally substituted 5 to 14-membered heteroaralkyl group, h) anoptionally substituted C₁₋₂₂ alkoxy group, i) an optionally substitutedunsaturated C₂₋₂₂ alkoxy group, j) an optionally substituted C₆₋₁₄aryloxy group or k) an optionally substituted 5 to 14-memberedheteroaryloxy group), 7) R^(S1)R^(S2)R^(S3)SiO— (wherein R^(S1), R^(S2)and R^(S3) are the same as or different from one another and eachrepresents a) a C₁₋₆ alkyl group or b) a C₆₋₁₄ aryl group), 8) a halogenatom, 9) R^(N1)R^(N2)N—R^(M)— (wherein R^(M) represents a) a singlebond, b) —CO—O—, c) —SO₂—O—, d) —CS—O— or e) —CO—NR^(N3)— (whereinR^(N3) represents a hydrogen atom or an optionally substituted C₁₋₆alkyl group), provided that each of the leftmost bond in b) to e) isbound to the nitrogen atom; and R^(N1) and R^(N2) are the same as ordifferent from each other and each represents a) a hydrogen atom, b) anoptionally substituted C₁₋₂₂ alkyl group, c) an optionally substitutedunsaturated C₂₋₂₂ alkyl group, d) an optionally substituted aliphaticC₂₋₂₂ acyl group, e) an optionally substituted aromatic C₇₋₁₅ acylgroup, f) an optionally substituted C₆₋₁₄ aryl group, g) an optionallysubstituted 5 to 14-membered heteroaryl group, h) an optionallysubstituted C₇₋₂₂ aralkyl group, i) an optionally substituted C₁₋₂₂alkylsulfonyl group, j) an optionally substituted C₆₋₁₄ arylsulfonylgroup, k) an optionally substituted 3 to 14-membered non-aromaticheterocyclic group formed by R^(N1) and R^(N2) together with thenitrogen atom to which R^(N1) and R^(N2) are bound, and the non-aromaticheterocyclic group may have substituents, l) an optionally substituted 5to 14-membered heteroaralkyl group, m) an optionally substituted C₃₋₁₄cycloalkyl group or n) an optionally substituted 3 to 14-memberednon-aromatic heterocyclic group), 10) R^(N4)SO₂—O— (wherein R^(N4)represents a) an optionally substituted C₁₋₂₂ alkyl group, b) anoptionally substituted C₆₋₁₄ aryl group, c) an optionally substitutedC₁₋₂₂ alkoxy group, d) an optionally substituted unsaturated C₂₋₂₂alkoxy group, e) an optionally substituted C₆₋₁₄ aryloxy group, f) anoptionally substituted 5 to 14-membered heteroaryloxy group, g) anoptionally substituted C₇₋₂₂ aralkyloxy group or h) an optionallysubstituted 5 to 14-membered heteroaralkyloxy group), 11)(R^(N5)O)₂PO—O— (wherein R^(N5) represents a) an optionally substitutedC₁₋₂₂ alkyl group, b) an optionally substituted unsaturated C₂₋₂₂ alkylgroup, c) an optionally substituted C₆₋₁₄ aryl group, d) an optionallysubstituted 5 to 14-membered heteroaryl group, e) an optionallysubstituted C₇₋₂₂ aralkyl group or f) an optionally substituted 5 to14-membered heteroaralkyl group), 12) (R^(N1)R^(N2)N)₂PO—O— (whereinR^(N1) and R^(N2) have the same meanings as defined above) or 13)(R^(N1)R^(N2)N)(R^(N5)O)PO—O— (wherein R^(N1), R^(N2) and R^(N5) havethe same meanings as defined above), provided that a compound in whichR³, R⁶, R⁷ and R²¹ are all hydroxyl groups, and a compound in which R³,R⁶ and R²¹ are all hydroxyl groups and R⁷ is an acetoxy group areexcluded), a pharmacologically acceptable salt thereof or a hydrate ofthem.
 2. The compound according to claim 1 represented by the formula(I-a):

(in the formula, R^(3a), R^(6a), R^(7a) and R^(21a) are the same as ordifferent from one another and each represents 1) a hydroxyl group or anoxo group formed together with the carbon atom to which each of R^(3a),R^(6a), R^(7a) and R^(21a) is bound, provided that R^(6a) is limited toa hydroxyl group, 2) an optionally substituted C₁₋₂₂ alkoxy group, 3)R^(a)CO—O— (wherein R^(a) represents a) a hydrogen atom, b) anoptionally substituted C₁₋₂₂ alkyl group, c) an optionally substitutedunsaturated C₂₋₂₂ alkyl group, d) an optionally substituted C₆₋₁₄ arylgroup, e) an optionally substituted 5 to 14-Membered heteroaryl group,f) an optionally substituted C₇₋₂₂ aralkyl group, g) an optionallysubstituted 5 to 14-membered heteroaralkyl group, h) an optionallysubstituted C₁₋₂₂ alkoxy group, i) an optionally substituted unsaturatedC₂₋₂₂ alkoxy group, j) an optionally substituted C₆₋₁₄ aryloxy group ork) an optionally substituted 5 to 14-membered heteroaryloxy group), 4)R^(aS1)R^(aS2)S^(aS3)SiO— (wherein R^(aS1), R_(aS2) and R^(aS3) are thesame as or different from one another and each represents a) a C₁₋₆alkyl group or b) a C₆₋₁₄ aryl group), 5) a halogen atom or 6)R^(aN1)R^(aN2)N—R^(aM)— (wherein R^(aM) represents a) a single bond, b)—CO—C—, c)—SO₂—O—, d) —CS—C— or e) —CO—NR^(aN3)— (wherein R^(aN3)represents a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup, provided that each of the leftmost bond in b) to e) is bound tothe nitrogen atom); and R^(aN1) and R^(aN2) are the same as or differentfrom each other and each represents a) a hydrogen atom, b) an optionallysubstituted C₁₋₂₂ alkyl group, c) an optionally substituted unsaturatedC₂₋₂₂ alkyl group, d) an optionally substituted aliphatic C₂₋₂ acylgroup, e) an optionally substituted aromatic C₇₋₁₅ acyl group, f) anoptionally substituted C₆₋₁₄ aryl group, g) an optionally substituted 5to 14-membered heteroaryl group, h) an optionally substituted C₇₋₂₂aralkyl group, i) an optionally substituted C₁₋₂₂ alkylsulfonyl group,j) an optionally substituted CO₁₄ arylsulfonyl group, k) an optionallysubstituted 3 to 14-membered non-aromatic heterocyclic group formed byR^(aN1) and R^(aN2) together with the nitrogen atom to which R^(aN1) andR^(aN2) are bound, and the non-aromatic heterocyclic group may havesubstituents, l) an optionally substituted 5 to 14-memberedheteroaralkyl group, m) an optionally substituted C₃₋₁₄ cycloalkyl groupor n) an optionally substituted 3 to 14-membered non-aromaticheterocyclic group)), a pharmacologically acceptable salt thereof or ahydrate of them.
 3. The compound according to claim 1 represented by theformula (I-b):

(in the formula, R^(3b, R) ^(3b), R^(7b) and R^(21b) are the same as ordifferent from one another and each represents 1) a hydroxyl group or anoxo group formed together with the carbon atom to which each of R^(3b),R^(6b), R^(7b) and R^(21b) is bound, provided that R^(6b) is limited toa hydroxyl group, 2) an optionally substituted C₁₋₂₂ alkoxy group, 3)R^(b)CO—O— (wherein R^(b) represents a) a hydrogen atom, b) anoptionally substituted C₁₋₂₂ alkyl group, c) an optionally substitutedunsaturated C₂₋₂₂ alkyl group, d) an optionally substituted C₆₋₁₄ arylgroup, e) an optionally substituted 5 to 14-membered heteroaryl group,f) an optionally substituted C₇₋₂₂ aralkyl group, g) an optionallysubstituted 5 to 14-membered heteroaralkyl group, h) an optionallysubstituted C₁₋₂₂ alkoxy group, i) an optionally substituted unsaturatedC₂₋₂₂ alkoxy group, j) an optionally substituted C₆₋₁₄ aryloxy group ork) an optionally substituted 5 to 14-membered heteroaryloxy group), 4)R^(bS1)R^(bS2)R^(bS3)SiO— (wherein R^(bS1), R^(bS2) and R^(bS3) are thesame as or different from one another and each represents a) a C₁₋₆alkyl group or b) a C₆₋₁₄ aryl group) or 5) R^(bN1)R^(bN2)N—R^(bM)—(wherein R^(bM) represents a) —CO—O— or b) —CS—O—, provided that each ofthe leftmost bond in a) and b) is bound to the nitrogen atom; andR^(bN1) and R^(bN2) are the same as or different from each other andeach represents a) a hydrogen atom, b) an optionally substituted C₁₋₂₂alkyl group, c) an optionally substituted unsaturated C₂₋₂₂ alkyl group,d) an optionally substituted aliphatic C₂₋₂₂ acyl group, e) anoptionally substituted aromatic C₇₋₁₅ acyl group, f) an optionallysubstituted C₆₋₁₄ aryl group, g) an optionally substituted 5 to14-membered heteroaryl group, h) an optionally substituted C₇₋₂₂ aralkylgroup, i) an optionally substituted C₁₋₂₂ alkylsulfonyl group, j) anoptionally substituted C₆₋₁₄ arylsulfonyl group, k) an optionallysubstituted 3 to 14-membered non-aromatic heterocyclic group formed byR^(bN1) and R^(bN2) together with the nitrogen atom to which R^(bN1) andR^(bN2) are bound, and the non-aromatic heterocyclic group may havesubstituents, l) an optionally substituted 5 to 14-memberedheteroaralkyl group, m) an optionally substituted C₃₋₁₄ cycloalkyl groupor n) an optionally substituted 3 to 14-membered non-aromaticheterocyclic group)), a pharmacologically acceptable salt thereof or ahydrate of them.
 4. The compound according to claim 1 represented by theformula (I-c):

(in the formula, R^(3c), R^(6c), R^(7c) and R^(21c) are the same as ordifferent from one another and each represents 1) a hydroxyl group or anoxo group formed together with the carbon atom to which each of R^(3c),R^(6c), R^(7c) and R^(21c) is bound, provided that R^(6c) is limited toa hydroxyl group, 2) an optionally substituted C₁₋₂₂ alkoxy group, 3)R^(c)CO—(wherein R^(c) represents a) an optionally substituted C₁₋₂₂alkyl group, b) an optionally substituted C₆₋₁₄ aryl group, c) anoptionally substituted C₇₋₂₂ aralkyl group or d) an optionallysubstituted C₆₋₁₄ aryloxy group), 4) R^(cS1)R^(cS2)R^(cS3)SiO— (whereinR^(cS1), R^(cS2) and R^(cS3) are the same as or different from oneanother and each represents a) a C₁₋₆ alkyl group or b) a C₆₋₁₄ arylgroup) or 5) R^(cN1) R^(cN2)N—R^(cM)— (wherein R^(cM) represents a)—CO—O— or b) —CS—O—, provided that each of the leftmost bond in a) andb) is bound to the nitrogen atom; and R^(cN1) and R^(cN2) are the sameas or different from each other and each represents a) a hydrogen atom,b) an optionally substituted C₁₋₂₂ alkyl group, c) an optionallysubstituted 3 to 14-membered non-aromatic heterocyclic group formed byR^(cN1) and R^(cN2) together with the nitrogen atom to which R^(cN1) andR^(cN2) are bound, and the non-aromatic heterocyclic group may havesubstituents, d) an optionally substituted 5 to 14-memberedheteroaralkyl group, e) an optionally substituted C₃₋₁₄ cycloalkyl groupor f) an optionally substituted 3 to 14-membered non-aromaticheterocyclic group)), a pharmacologically acceptable salt thereof or ahydrate of them.
 5. The compound according to claim 1 represented by theformula (I-d):

(in the formula, R^(3d) represents 1) a hydroxyl group or an oxo groupformed together with the carbon atom to which R^(3d) is bound, 2) anoptionally substituted C₁₋₂₂ alkoxy group, 3) an optionally substitutedunsaturated C₂₋₂₂ alkoxy group, 4) an optionally substituted C₇₋₂₂aralkyloxy group, 5) R^(d)CO—O— (wherein R^(d) represents a) a hydrogenatom, b) an optionally substituted C₁₋₂₂ alkyl group, c) an optionallysubstituted unsaturated C₂₋₂₂ alkyl group, d) an optionally substitutedC₆₋₁₄ aryl group, e) an optionally substituted 5 to 14-memberedheteroaryl group, f) an optionally substituted C₇₋₂₂ aralkyl group, g)an optionally substituted 5 to 14-membered heteroaralkyl group, h) anoptionally substituted C₁₋₂₂ alkoxy group, i) an optionally substitutedunsaturated C₂₋₂₂ alkoxy group, j) an optionally substituted C₆₋₁₄aryloxy group or k) an optionally substituted 5 to 14-memberedheteroaryloxy group) or 6) R^(dN1)R^(dN2)N—CO—C— (wherein R^(dN1) andR^(dN2) are the same as or different from each other and each representsa) a hydrogen atom, b) an optionally substituted C₁₋₂₂ alkyl group, c)an optionally substituted unsaturated C₂₋₂₂ alkyl group, d) anoptionally substituted C₆₋₁₄ aryl group, e) an optionally substituted 5to 14-membered heteroaryl group, f) an optionally substituted C₇₋₂₂aralkyl group, g) an optionally substituted 5 to 14-memberedheteroaralkyl group, h) an optionally substituted C₃₋₁₄ cycloalkylgroup, i) an optionally substituted 3 to 14-membered non-aromaticheterocyclic group or j) an optionally substituted 3 to 14-memberednon-aromatic heterocyclic group formed by R^(dN1) and R^(dN2) togetherwith the nitrogen atom to which R^(dN1) and R^(dN2) are bound, and thenon-aromatic heterocyclic group may have substituents); and R^(6d),R^(7d) and R^(21d) are the same as or different from one another andeach represents 1) a hydroxyl group or an oxo group formed together withthe carbon atom to which each of R^(6d), R^(7d) and R^(21d) is bound,provided that R^(6d) is limited to a hydroxyl group, 2) an optionallysubstituted C₁₋₂₂ alkoxy group, 3) an optionally substituted unsaturatedC₂₋₂₂ alkoxy group, 4) an optionally substituted C₇₋₂₂ aralkyloxy group,5) R^(d)CO—O— (wherein R^(d) has the same meaning as defined above), 6)R^(dN1)R^(dN2)N—CO—(wherein R^(dN1) and R^(dN2) have the same meaningsas defined above), 7) R^(dN1)R^(dN2)N—SO₂—O— (wherein R^(dN1) andR^(dN2) have the same meanings as defined above), 8)R^(dN1)R^(dN2)N—CS-0 (wherein R^(dN1) and R^(dN2) have the same meaningsas defined above), 9) R^(dN3)SO₂—O— (wherein R^(dN3) represents a) anoptionally substituted C₁₋₂₂ alkyl group, b) an optionally substitutedC₁₋₂₂ alkoxy group, c) an optionally substituted unsaturated C₂₋₂₂alkoxy group, d) an optionally substituted C₆₋₁₄ aryl group, e) anoptionally substituted C₆₋₁₄ aryloxy group, f) an optionally substituted5 to 14-membered heteroaryloxy group, g) an optionally substituted C₇₋₂₂aralkyloxy group or h) an optionally substituted 5 to 14-memberedheteroaralkyloxy group), 10) (R^(dN5)O)₂PO— (wherein R^(dN5) representsa) an optionally substituted C₁₋₂₂ alkyl group, b) an optionallysubstituted unsaturated C₂₋₂₂, alkyl group, c) an optionally substitutedC₆₋₁₄ aryl group, d) an optionally substituted 5 to 14-memberedheteroaryl group, e) an optionally substituted C₇₋₂₂ aralkyl group or f)an optionally substituted 5 to 14-membered heteroaralkyl group), 11)(R^(dN1)R^(dN2)N)₂PO— (wherein R^(dN1) and R^(dN2) have the samemeanings as defined above) or 12) (R^(dN1)R^(dN2)N)(R^(dN5)O)PO—(wherein R^(dN1), R^(dN2) and R^(dN5) have the same meanings as definedabove), provided that a compound in which R^(3d), R^(6d), R^(7d) andR^(21d) are all hydroxyl groups, and a compound in which R^(3d), R^(6d)and R^(21d) are hydroxyl groups and R^(7d) is an acetoxy group areexcluded), a pharmacologically acceptable salt thereof or a hydrate ofthem.
 6. The compound according to claim 1, wherein R⁶ and/or R⁷represents R^(N1)R^(N2)N—R^(M)— (wherein R^(M) represents a) —CO—C— orb) —CS—O—; and R^(N1) and R^(N2) have the same meanings as definedabove, provided that each of the leftmost bond in a) and b) is bound tothe nitrogen atom), a pharmacologically acceptable salt thereof or ahydrate of them.
 7. The compound according to claim 1, apharmacologically acceptable salt thereof or a hydrate of them, whereinR²¹ is an oxo group formed together with the carbon atom to which R²¹ isbound.
 8. The compound according to claim 5 represented by the formula(I-e):

(in the formula, R^(3e) and R^(21e) are the same as or different fromeach other and each represents 1) a hydroxyl group or an oxo groupformed together with the carbon atom to which each of R^(3e) and R^(21e)is bound, 2) an optionally substituted C₁₋₆ alkoxy group, 3) anoptionally substituted unsaturated C₂₋₁₀ alkoxy group, 4) an optionallysubstituted C₇₋₁₀ aralkyloxy group, 5) an optionally substitutedaliphatic C₂₋₆ acyloxy group or 6) R^(eN1)R^(eN2)N—CO—(wherein R^(eN1)and R^(eN2) are the same as or different from each other and eachrepresents A) a hydrogen atom or B) an optionally substituted C₁₋₆ alkylgroup); and R^(6e) and R^(7e) are the same as or different from eachother and each represents 1) a hydroxyl group or an oxo group formedtogether with the carbon atom to which each of R^(6e) and R^(7e) isbound, provided that R^(6e) is limited to a hydroxyl group, 2) anoptionally substituted C₁₋₆ alkoxy group, 3) an optionally substitutedunsaturated C₂₋₁₀ alkoxy group, 4) an optionally substituted C₇₋₁₀aralkyloxy group, 5) an optionally substituted aliphatic C₂₋₆ acyloxygroup or 6) R^(e)C(═Y^(e))—O— (wherein Y^(e) represents an oxygen atomor a sulfur atom; and R^(e) represents a) a hydrogen atom, b) anoptionally substituted C₁₋₆ alkyl group, c) an optionally substitutedC₇₋₁₀ aralkyl group, d) an optionally substituted 5 to 14-memberedheteroaralkyl group, e) the formula (III):

(in the formula, A) n represents an integer of 0 to 4; X_(e) representsi) —CHR^(eN4)—, ii) —NR^(eN5)—, iii) —O—, iv) —S—, v) —SO— or vi) —SO₂—;R^(eN1) represents i) a hydrogen atom or ii) a C₁₋₆ alkyl group; R^(eN2)represents i) a hydrogen atom or ii) a C₁₋₆ alkyl group; R^(eN3) andR^(eN4) are the same as or different from each other and each representsi) a hydrogen atom, ii) an optionally substituted C₁₋₆ alkyl group, iii)an optionally substituted unsaturated C₂₋₁₀ alkyl group, iv) anoptionally substituted C₆₋₁₄ aryl group, v) an optionally substituted 5to 14-membered heteroaryl group, vi) an optionally substituted C₇₋₁₀aralkyl group, vii) an optionally substituted C₃₋₈ cycloalkyl group,viii) an optionally substituted C₄₋₉ cycloalkyl alkyl group, ix) anoptionally substituted 5 to 14-membered heteroaralkyl group, x) anoptionally substituted 5 to 14-membered non-aromatic heterocyclic group,xi) —NR^(eN6)R^(eN1) (wherein R^(eN6) and R^(eN7) are the same as ordifferent from each other and each represents a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group) or xii) an optionallysubstituted 5 to 14-membered non-aromatic heterocyclic group formed byR^(eN3) and R^(eN4) together with the carbon atom to which R^(eN3) andR^(eN4) are bound, and the non-aromatic heterocyclic group may havesubstituents; and R^(eN5) represents i) a hydrogen atom, ii) anoptionally substituted C₁₋₆ alkyl group, iii) an optionally substitutedunsaturated C₂₋₁₀ alkyl group, iv) an optionally substituted C₆₋₁₄ arylgroup, v) an optionally substituted 5 to 14-membered heteroaryl group,vi) an optionally substituted C₇₋₁₀ aralkyl group, vii) an optionallysubstituted C₃₋₈ cycloalkyl group, viii) an optionally substituted C₄₋₉cycloalkyl alkyl group, ix) an optionally substituted 5 to 14-memberedheteroaralkyl group, x) an optionally substituted 5 to 14-memberednon-aromatic heterocyclic group or xi) an optionally substituted 5 to14-membered non-aromatic heterocyclic group formed by R^(eN3) andR^(eN5) together with the nitrogen atom to which R^(eN3) and R_(eN5) arebound, and the non-aromatic heterocyclic group may have substituents, B)X_(e), n, R^(eN3), R^(eN4) and R^(eN5) each represents the group asdefined above; and R_(eN1) and R^(eN2) together form an optionallysubstituted 5 to 14-membered non-aromatic heterocyclic group, C) X_(e),n, R_(eN2), R^(eN4) and R^(eNn5) each represents the group as definedabove; and R^(eN1) and R_(eN3) together form an optionally substituted 5to 14-membered non-aromatic heterocyclic group or D) X_(e), n, R^(eN1),R^(eN4) and R^(eN5) each represents the group as defined above; andR^(eN2) and R^(eN3) together form an optionally substituted 5 to14-membered non-aromatic heterocyclic group) or f) the formula (IV):

(in the formula, R^(eN8) and R^(eN9) are the same as or different fromeach other and each represents i) a hydrogen atom, ii) an optionallysubstituted C₁₋₆ alkyl group, iii) an optionally substituted C₆₋₁₄ arylgroup, iv) an optionally substituted 5 to 14-membered heteroaryl group,v) an optionally substituted C₇₋₁₀ aralkyl group or vi) an optionallysubstituted 5 to 14-membered heteroaralkyl group))), a pharmacologicallyacceptable salt thereof or a hydrate of them.
 9. The compound accordingto claim 5, wherein R^(6d) and/or R^(7d) represents R^(d1)C(═Y_(d1))—O—(wherein Y^(d1) represents an oxygen atom or a sulfur atom; and R^(d1)represents 1) a hydrogen atom, 2) an optionally substituted C₁₋₆ alkylgroup, 3) an optionally substituted C₇₋₁₀ aralkyl group or 4) anoptionally substituted 5 to 14-membered heteroaralkyl group), apharmacologically acceptable salt thereof or a hydrate of them.
 10. Thecompound according to claim 5, wherein R^(6d) and/or R^(7d) representsR^(d2)C(═Y^(d2))—O— (wherein Y^(d2) represents an oxygen atom or sulfuratom; and R^(d2) represents the formula (III′):

(in the formula, n represents an integer of 0 to 4; X₁ represents 1)—CHR^(dN7)—, 2) —NR^(dN8)—, 3) —O—, 4) —S—, 5) —SO— or 6) —SO₂—; R^(dN4)and R^(dN5) are the same as or different from each other and eachrepresents 1) a hydrogen atom or 2) a C₁₋₆ alkyl group; R^(dN6) andR^(dN7) are the same as or different from each other and eachrepresents 1) a hydrogen atom, 2) an optionally substituted C₁₋₆ alkylgroup, 3) an optionally substituted unsaturated C₂₋₁₀ alkyl group, 4) anoptionally substituted C₆₋₁₄ aryl group, 5) an optionally substituted 5to 14-membered heteroaryl group, 6) an optionally substituted C₇₋₁₀aralkyl group, 7) an optionally substituted C₃₋₈ cycloalkyl group, 8) anoptionally substituted C₄₋₉ cycloalkyl alkyl group, 9) an optionallysubstituted 5 to 14-membered heteroaralkyl group, 10) an optionallysubstituted 5 to 14-membered non-aromatic heterocyclic group, 11)—NR^(dN9)R^(dN10) (wherein R^(dN9) and R^(dN10) are the same as ordifferent from each other and each represents a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group) or 12) an optionallysubstituted 5 to 14-membered non-aromatic heterocyclic group formedtogether by R^(dN6) and R^(dN7), and the non-aromatic heterocyclic groupmay have substituents; and R^(dN8) represents 1) a hydrogen atom, 2) anoptionally substituted C₁₋₆ alkyl group, 3) an optionally substitutedunsaturated C₂₋₁₀ alkyl group, 4) an optionally substituted C₆₋₁₄ arylgroup, 5) an optionally substituted 5 to 14-membered heteroaryl group,6) an optionally substituted C₇₋₁₀ aralkyl group, 7) an optionallysubstituted C₃₋₈ cycloalkyl group, 8) an optionally substituted C₄₋₉cycloalkyl alkyl group, 9) an optionally substituted 5 to 14-memberedheteroaralkyl group, 10) an optionally substituted 5 to 14-memberednon-aromatic heterocyclic group, 11) an optionally substituted 5 to14-membered non-aromatic heterocyclic group formed by R^(dN4), R^(dN5)or R^(dN6) together with the nitrogen atom to which each of R^(dN4),R^(dN5) and R^(dN6) is bound, and the non-aromatic heterocyclic groupmay have substituents or 12) an optionally substituted 5 to 14-memberednon-aromatic heterocyclic group formed by two substituents selected fromthe group consisting of R^(dN4), R^(dN5) and R^(dN6) together with thenitrogen atom to which it is bound, and the non-aromatic heterocyclicgroup may have substituents)), a pharmacologically acceptable saltthereof or a hydrate of them.
 11. The compound according to claim 10, apharmacologically acceptable salt thereof or a hydrate of them, whereinX₁ represents —NR^(dN8)— (wherein NR^(dN8) has the same meanings asdefined above).
 12. The compound according to claim 5 represented by theformula (I-f):

(in the formula, R^(7f) represents R^(f)C(═Y^(f))—O— (wherein Y^(f)represents an oxygen atom or a sulfur atom; and R^(f) represents theformula (V):

(wherein n represents an integer of 0 to 4; R^(fN1) represents 1) ahydrogen atom, 2) a methyl group or 3) an ethyl group; and R^(fN2)represents 1) a hydrogen atom, 2) a methylamino group, 3) adimethylamino group, 4) an ethylamino group, 5) a diethylamino group, 6)an ethylmethylamino group, 7) a pyridinyl group, 8) a pyrrolidin-1-ylgroup, 9) a piperidin-1-yl group, 10) a morpholin-4-yl group or 11) a4-methylpiperazin-1-yl group))), a pharmacologically acceptable saltthereof or a hydrate of them.
 13. The compound according to claim 5,wherein R^(6d) and/or R^(7d) represents R^(d3)CO—O— (wherein R^(d3)represents the formula (VI):

(wherein n₁ and n₂ are the same as or different from each other and eachrepresents an integer of 0 to 4; X₂ represents 1) —CHR^(dN13)—, 2)—NR^(dN14)—, 3) —O—, 4) —S—, 5) —SO— or 6) —SO₂—; R^(dN11) represents 1)a hydrogen atom or 2) an optionally substituted C₁₋₆ alkyl group;R^(dN12) represents 1) a hydrogen atom, 2) an optionally substitutedC₁₋₆ alkyl group, 3) an optionally substituted C₆₋₁₄ aryl group or 4) anoptionally substituted C₇₋₁₀ aralkyl group; R^(dN13) represents 1) ahydrogen atom, 2) an optionally substituted C₁₋₆ alkyl group, 3) anoptionally substituted unsaturated C₂₋₁₀ alkyl group, 4) an optionallysubstituted C₆₋₁₄ aryl group, 5) an optionally substituted 5 to14-membered heteroaryl group, 6) an optionally substituted C₇₋₁₀ aralkylgroup, 7) an optionally substituted C₃₋₈ cycloalkyl group, 8) anoptionally substituted C₄₋₉ cycloalkyl alkyl group, 9) an optionallysubstituted 5 to 14-membered heteroaralkyl group, 10) —NR^(dN15)R^(dN16)(wherein R^(dN15) and R^(dN16) are the same as or different from eachother and each represents a hydrogen atom or an optionally substitutedC₁₋₆ alkyl group) or 11) an optionally substituted 5 to 14-memberednon-aromatic heterocyclic group; and R^(dN14) represents 1) a hydrogenatom, 2) an optionally substituted C₁₋₆ alkyl group, 3) an optionallysubstituted unsaturated C₂₋₁₀ alkyl group, 4) an optionally substitutedC₆₋₁₄ aryl group, 5) an optionally substituted 5 to 14-memberedheteroaryl group, 6) an optionally substituted C₇₋₁₀ aralkyl group, 7)an optionally substituted C₃₋₈ cycloalkyl group, 8) an optionallysubstituted C₄₋₉ cycloalkyl alkyl group, 9) an optionally substituted 5to 14-membered heteroaralkyl group or 10) an optionally substituted 5 to14-membered non-aromatic heterocyclic group)), a pharmacologicallyacceptable salt thereof or a hydrate of them.
 14. The compound accordingto claim 5 represented by the formula (I-g):

(in the formula, R^(7g) represents R^(g)CO—O— (wherein R^(g) representsthe formula (VII):

(wherein n₃ represents 1 or 2; R^(dN17) represents 1) a hydrogen atom,2) a methyl group or 3) an ethyl group; and R^(dN18) represents 1) ahydrogen atom, 2) a methyl group or 3) an ethyl group))), apharmacologically acceptable salt thereof or a hydrate of them.
 15. Thecompound according to claim 5, wherein R^(6d) and/or R^(7d) representsR^(d4)CO—O— (wherein R^(d4) represents the formula (VIII):

(wherein n₁ and n₂ are the same as or different from each other and eachrepresents an integer of 0 to 4; X₃ represents 1) —CHR^(dN21)—, 2)—NR^(dN22)—, 3) —O—, 4) —S—, 5) —SO— or 6) —SO₂—; R^(dN19) represents 1)a hydrogen atom or 2) a C₁₋₆ alkyl group; R^(dN20) represents 1) ahydrogen atom, 2) an optionally substituted C₁₋₆ alkyl group, 3) anoptionally substituted C₆₋₁₄ aryl group or 4) an optionally substitutedC₇₋₁₀ aralkyl group; R^(dN21) represents 1) a hydrogen atom, 2) anoptionally substituted C₁₋₆ alkyl group, 3) an optionally substitutedunsaturated C₂₋₁₀ alkyl group, 4) an optionally substituted C₁₋₆ alkoxygroup, 5) an optionally substituted C₆₋₁₄ aryl group, 6) an optionallysubstituted 5 to 14-membered heteroaryl group, 7) an optionallysubstituted C₇₋₁₀ aralkyl group, 8) an optionally substituted C₃₋₈cycloalkyl group, 9) an optionally substituted C₄₋₉ cycloalkyl alkylgroup, 10) an optionally substituted 5 to 14-membered heteroaralkylgroup, 11) —NR^(dN23)R^(dN24) (wherein R^(dN23) and R^(dN24) are thesame as or different from each other and each represents a hydrogen atomor an optionally substituted C₁₋₆ alkyl group) or 12) an optionallysubstituted 5 to 14-membered non-aromatic heterocyclic group; andR^(dN22) represents 1) a hydrogen atom, 2) an optionally substitutedC₁₋₆ alkyl group, 3) an optionally substituted unsaturated C₂₋₁₀ alkylgroup, 4) an optionally substituted C₆₋₁₄ aryl group, 5) an optionallysubstituted 5 to 14-membered heteroaryl group, 6) an optionallysubstituted C₇₋₁₀ aralkyl group, 7) an optionally substituted C₃₋₈cycloalkyl group, 8) an optionally substituted C₄₋₉ cycloalkyl alkylgroup, 9) an optionally substituted 5 to 14-membered heteroaralkyl groupor 10) an optionally substituted 5 to 14-membered non-aromaticheterocyclic group)), a pharmacologically acceptable salt thereof or ahydrate of them.
 16. The compound according to claim 5 represented bythe formula (I-h):

(in the formula, R^(7h) represents R^(h)CO—O— (wherein R^(h) representsthe formula (IX):

(wherein n₄ represents an integer of 1 to 3; and R^(dN25) represents 1)an amino group, 2) a methylamino group, 3) a dimethylamino group, 4) apyrrolidin-1-yl group, 5) a piperidin-1-yl group or 6) a morpholin-4-ylgroup))), a pharmacologically acceptable salt thereof or a hydrate ofthem.
 17. The compound according to claim 5 represented by the formula(I-i):

(in the formula, R^(7i) represents R^(i)CO—O— (wherein R^(i) representsthe formula (X):

(wherein n₄ represents an integer of 1 to 3; R^(dN26) represents 1) ahydrogen atom, 2) an optionally substituted C₁₋₆ alkyl group, 3) anoptionally substituted C₆₋₁₄ aryl group or 4) an optionally substitutedC₇₋₁₀ aralkyl group; and R^(dN27) represents 1) a hydrogen atom, 2) anoptionally substituted C₁₋₆ alkyl group, 3) an optionally substitutedC₃₋₈ cycloalkyl group, 4) an optionally substituted 3 to 8-memberednon-aromatic heterocyclic group, 5) an optionally substituted C₆₋₁₄ arylgroup, 6) an optionally substituted 5 to 14-membered heteroaryl group,7) an optionally substituted C₇₋₁₀ aralkyl group, 8) an optionallysubstituted 5 to 14-membered heteroaralkyl group or 9) an optionallysubstituted C₄₋₉ cycloalkyl alkyl group))), a pharmacologicallyacceptable salt thereof or a hydrate of them.
 18. The compound accordingto claim 5 represented by the formula (I-j):

(in the formula, R^(7j) represents R^(j)CO—O— (wherein R^(j) representsthe formula (XI):

(wherein n₄ represents an integer of 1 to 3; and R^(dN28) represents 1)a hydrogen atom, 2) an optionally substituted C₁₋₆ alkyl group, 3) aC₃₋₈ cycloalkyl group, 4) a C₄₋₉ cycloalkyl alkyl group, 5) a C₇₋₁₀aralkyl group, 6) a pyridinyl group or 7) a tetrahydropyranyl group))),a pharmacologically acceptable salt thereof or a hydrate of them. 19.The compound according to claim 5 represented by the formula (I-k):

(in the formula, R^(7k) represents R^(k)CO—O— (wherein R^(k) representsthe formula (XII):

(wherein m₁, m₂, m₃ and m₄ are the same as or different from one anotherand each represents 0 or 1; n₄ represents an integer of 1 to 3; andR^(dN29) represents 1) a hydrogen atom, 2) an optionally substitutedC₁₋₆ alkyl group, 3) an optionally substituted unsaturated C₂₋₁₀ alkylgroup, 4) an optionally substituted C₆₋₁₄ aryl group, 5) an optionallysubstituted 5 to 14-membered heteroaryl group, 6) an optionallysubstituted C₇₋₁₀ aralkyl group, 7) an optionally substituted C₃₋₈cycloalkyl group, 8) an optionally substituted C₄₋₉ cycloalkyl alkylgroup, 9) an optionally substituted 5 to 14-membered heteroaralkyl groupor 10) an optionally substituted 5 to 14-membered non-aromaticheterocyclic group))), a pharmacologically acceptable salt thereof or ahydrate of them.
 20. The compound according to claim 5 represented bythe formula (I-m):

(in the formula, R^(7m) represents R^(m)CO—O— (wherein R^(m) representsthe formula (XIII):

(wherein m₅ represents an integer of 1 to 3; and n₅ represents 2 or3))), a pharmacologically acceptable salt thereof or a hydrate of them.21. The compound according to claim 5 represented by the formula (I-n):

(in the formula, R^(7n) represents R^(n)CO—O— (wherein R^(n) is a grouprepresented by the formula (XIV):

a pharmacologically acceptable salt thereof or a hydrate of them. 22.The compound according to claim 1, which is selected from:(8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(SE,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxyticosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-thien-11-olide;(8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)oxy-18,19-epoxytricosa-5,12,14-trien-11-olide;(8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;and(8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide.23. The compound according to claim 1, which is selected from:(8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;(8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide;and(8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide.24. A medicament comprising the compound according to claim 1, apharmacologically acceptable salt thereof or a hydrate of them as anactive ingredient.
 25. A pharmaceutical composition comprising thecompound according to claim 1, a pharmacologically acceptable saltthereof or a hydrate of them as an active ingredient.
 26. The medicamentaccording to claim 24, which is an agent for preventing or treating adisease against which a regulation of gene expression is efficacious.27. The medicament according to claim 24, which is an agent forpreventing or treating a diseases against which suppression of VEGFproduction is efficacious.
 28. The medicament according to claim 24,which is an agent for preventing or treating a disease against which anantiangiogenic effect is efficacious.
 29. The medicament according toclaim 24, which is an angiogenesis inhibitor.
 30. The medicamentaccording to claim 24, which is an antitumor agent.
 31. The medicamentaccording to claim 24, as a therapeutic agent for treating angioma. 32.The medicament according to claim 24, which is a cancer metastasisinhibitor.
 33. The medicament according to claim 24, which is atherapeutic agent for treating retinal neovascularization or diabeticretinopathy.
 34. The medicament according to claim 24, which is atherapeutic agent for treating inflammatory disease.
 35. The medicamentaccording to claim 24, which is a therapeutic agent for treatinginflammatory diseases consisting of deformans arthritis, rheumatoidarthritis, psoriasis and delayed hypersensitivity reaction.
 36. Themedicament according to claim 24, which is a therapeutic agent fortreating atherosclerosis.
 37. The medicament according to claim 24,which is a therapeutic agent for treating solid cancer.
 38. Themedicament according to claim 37, wherein the solid cancer is lungcancer, brain tumor, breast cancer, prostate cancer, ovarian cancer,colon cancer or melanoma.
 39. The medicament according to claim 24,which is a therapeutic agent for treating leukemia.
 40. The medicamentaccording to claim 24, which is an antitumor agent based on a regulationof gene expression.
 41. The medicament according to claim 24, which isan antitumor agent based on suppression of VEGF production.
 42. Themedicament according to claim 24, which is an antitumor agent based onan effect of angiogenesis inhibition.
 43. A method for preventing ortreating a disease against which a regulation of gene expression isefficacious, which comprises administering the compound according toclaim 1, a pharmacologically acceptable salt thereof or a hydrate ofthem as an active ingredient to a patient.
 44. A method for preventingor treating a disease against which suppression of VEGF production isefficacious, which comprises administering the compound according toclaim 1, a pharmacologically acceptable salt thereof or a hydrate ofthem as an active ingredient to a patient.
 45. A method for preventingor treating a disease against which an angiogenesis inhibition isefficacious, which comprises administering the compound according toclaim 1, a pharmacologically acceptable salt thereof or a hydrate ofthem as an active ingredient to a patient.
 46. The method for preventingor treating cancer according to claim
 43. 47. The method for preventingor treating leukemia according to claim
 43. 48. The method forpreventing or treating angioma according to claim
 44. 49. The method forpreventing or treating a cancer metastasis according to claim
 44. 50.The method for preventing or treating retinal neovascularization ordiabetic retinopathy according to claim
 44. 51. The method forpreventing or treating inflammatory disease according to claim
 44. 52.The method for preventing or treating inflammatory diseases consistingof deformans arthritis, rheumatoid arthritis, psoriasis and delayedhypersensitivity reaction according to claim
 44. 53. The method forpreventing or treating atherosclerosis according to claim
 44. 54. Themethod for preventing or treating solid cancer according to claim 46.55. The method for preventing or treating the solid cancer which is lungcancer, brain tumor, breast cancer, prostate cancer, ovarian cancer,colon cancer or melanoma according to claim
 54. 56. The method forpreventing or treating cancer based on a regulation of gene expressionaccording to claim
 43. 57. The method for preventing or treating cancerbased on suppression of VEGF production according to claim
 44. 58. Themethod for preventing or treating cancer based on an effect ofangiogenesis inhibition according to claim 45